Italian War of 1521 – 26 The Italian War of 1521 – 26 , sometimes known as the Four Years ' War , was a part of the Italian Wars . The war pitted Francis I of France and the Republic of Venice against the Holy Roman Emperor Charles V , Henry VIII of England , and the Papal States . The conflict arose from animosity over the election of Charles as Emperor in 1519 – 20 and from Pope Leo X ' s need to ally with Charles against Martin Luther . The war broke out across Western Europe late in 1521 when a French - backed Gascon - Navarrese expedition tried to reconquer Navarre , while the French launched an attack on the Low Countries . Charles I ' s Spanish army struck back up to the Pyrenees , and other forces attacked northern France , where they were stopped in turn . The Pope , the Emperor , and Henry VIII then signed a formal alliance against France , and hostilities began on the Italian Peninsula . At the Battle of Bicocca , Imperial and Papal forces defeated the French , driving them from Lombardy . Following the battle , fighting again spilled onto French soil , while Venice made a separate peace . The English invaded France in 1523 , while Charles de Bourbon , alienated by Francis ' s attempts to seize his inheritance , betrayed Francis and allied himself with the Emperor . A French attempt to regain Lombardy in 1524 failed and provided Bourbon with an opportunity to invade Provence at the head of a Spanish army . Francis himself led a second attack on Milan in 1525 . While he was initially successful in driving back the Spanish and Imperial forces , his disastrous defeat at the Battle of Pavia , where he was captured and many of his chief nobles were killed , led to the end of the war . With Francis imprisoned in Spain , a series of diplomatic maneuvers centered around his release ensued , including a special French mission sent by Francis ' mother Louise of Savoy to the court of Suleiman the Magnificent that would result in an Ottoman ultimatum to Charles — an unprecedented alliance between Christian and Muslim monarchs that would cause a scandal in the Christian world . Suleiman used the opportunity to invade Hungary in the summer of 1526 , defeating Charles ' allies at the Battle of Mohács ; but , despite these efforts , Francis would sign the Treaty of Madrid , surrendering his claims to Italy , Flanders , and Burgundy . Only a few weeks after his release , however , he repudiated the terms of the treaty , starting the War of the League of Cognac . Although the Italian Wars would continue for another three decades , they would end with France having failed to regain any substantial territories in Italy . Prelude . By 1518 , the peace that had prevailed in Europe after the Battle of Marignano was beginning to crumble . The major powers ( France , England , Spain , and the Holy Roman Empire ) were outwardly friendly , pledging by the Treaty of London to come to the aid of any of the signatories that was attacked and to combine against any nation that broke the peace . They were divided , however , on the question of the Imperial succession . The Holy Roman Emperor , Maximilian I , intending for a Habsburg to succeed him , began to campaign on behalf of Charles of Spain , while Francis put himself forward as an alternate candidate . At the same time , the Papacy and the Holy Roman Empire were forced to deal with the rising influence of Martin Luther , who found support among some Imperial nobles , while Francis was faced with Cardinal Thomas Wolsey , who interposed himself into the quarrels of the continent in an attempt to increase both England ' s influence and his own . Maximilian ' s death in 1519 brought the Imperial election to the forefront of European politics . Pope Leo X , threatened by the presence of Spanish troops a mere forty miles from the Vatican , supported the French candidacy . The prince - electors themselves , with the exception of Frederick of Saxony , who refused to countenance the campaigning , promised their support to both candidates at once . Before his death , Maximilian had already promised sums of 500 , 000 florins to the Electors in exchange for their votes , but Francis offered up to three million , and Charles retaliated by borrowing vast sums from the Fuggers . The final outcome , however , was not determined by the exorbitant bribes , which included Leo promising to make the Archbishop of Mainz his permanent legate . The general outrage of the populace at the idea of a French Emperor gave the Electors pause , and when Charles put an army in the field near Frankfurt , where they were meeting , the Electors obligingly voted for him . He was crowned Holy Roman Emperor on 23 October 1520 , by which point he already controlled both the Spanish crown and the hereditary Burgundian lands in the Low Countries . Cardinal Wolsey , hoping to increase Henry VIII ' s influence on the continent , offered the services of England as a mediator for the various disputes between Francis and Charles . Henry and Francis staged an extravagant meeting at the Field of the Cloth of Gold . Immediately afterwards , Wolsey entertained Charles in Calais . Following the meetings , Wolsey , concerned mainly with improving his own stature in preparation for the next papal conclave , proceeded to stage a hollow arbitration conference at Calais , which lasted until April 1522 to no practical effect . In December , the French began to plan for war . Francis did not wish to openly attack Charles because Henry had announced his intention to intervene against the first party to break the tenuous peace . Instead , he turned to more covert support for incursions into Imperial and Spanish territory . One attack would be made on the Meuse River , under the leadership of Robert de la Marck . Simultaneously , a French - Navarrese army would advance through Navarre after reconquering St - Jean - Pied - de - Port . The expedition was nominally led by the 18 - year - old Navarrese king Henry d ' Albret , whose kingdom had been invaded by Ferdinand II of Aragon in 1512 , but the army was effectively commanded by André de Foix and funded and equipped by the French . The French designs quickly proved flawed as the intervention of Henry of Nassau drove back the Meuse offensive ; and although de Foix was initially successful in seizing Pamplona , he was driven from Navarre after being defeated at the Battle of Esquiroz on 30 June 1521 . Charles was meanwhile preoccupied with the issue of Martin Luther , whom he confronted at the Diet of Worms in March 1521 . The Emperor , who did not know German , viewed Catholicism as a natural way of binding the diverse principalities of the Holy Roman Empire to him . Since Pope Leo X , for his part , was unwilling to tolerate such open defiance of his own authority , he and the Emperor were forced to support one another against Luther , who was now backed by Frederick of Saxony and Franz von Sickingen . On 25 May 1521 , Charles and Cardinal Girolamo Aleandro , the Papal nuncio , proclaimed the Edict of Worms against Luther . Simultaneously , the Emperor promised the Pope the restoration of Parma and Piacenza to the Medici and of Milan to the Sforza . Leo , needing the Imperial mandate for his campaign against what he viewed as a dangerous heresy , promised to assist in expelling the French from Lombardy , leaving Francis with only the Republic of Venice for an ally . Initial moves . In June , Imperial armies under Henry of Nassau invaded the north of France , razing the cities of Ardres and Mouzon and besieging Tournai . They were delayed by the dogged resistance of the French , led by Pierre Terrail , Seigneur de Bayard and Anne de Montmorency , during the Siege of Mezieres , which gave Francis time to gather an army to confront the attack . On 22 October 1521 , Francis encountered the main Imperial army , which was commanded by Charles V himself , near Valenciennes . Despite the urging of Charles de Bourbon , Francis hesitated to attack , which allowed Charles time to retreat . When the French were finally ready to advance , the start of heavy rains prevented an effective pursuit and the Imperial forces were able to escape without a battle . Shortly afterwards , French - Navarrese troops under Bonnivet and Claude of Lorraine seized the key city of Fuenterrabia , at the mouth of the Bidasoa River on the Franco - Spanish border , following a protracted series of maneuvers , providing the French with an advantageous foothold in northern Spain that would remain in their hands for the next two years . By November , the French situation had deteriorated considerably . Charles , Henry VIII , and the Pope signed an alliance against Francis on 28 November . Odet de Foix , Vicomte de Lautrec , the French governor of Milan , was tasked with resisting the Imperial and Papal forces ; he was outmatched by Prospero Colonna , however , and by late November had been forced out of Milan and had retreated to a ring of towns around the Adda River . There , Lautrec was reinforced by the arrival of fresh Swiss mercenaries ; but , having no money available to pay them , he gave in to their demands to engage the Imperial forces immediately . On 27 April 1522 , he attacked Colonna ' s combined Imperial and Papal army near Milan at the Battle of Bicocca . Lautrec had planned to use his superiority in artillery to his advantage , but the Swiss , impatient to engage the enemy , masked his guns and charged against the entrenched Spanish arquebus iers . In the resulting melee , the Swiss were badly mauled by the Spanish under Fernando d ' Avalos , Marquess of Pescara , and by a force of landsknechts commanded by Georg Frundsberg . Their morale broken , the Swiss returned to their canton s ; Lautrec , left with too few troops to continue the campaign , abandoned Lombardy entirely . Colonna and d ' Avalos , left unopposed , proceeded to besiege Genoa , capturing the city on 30 May . France at bay . Lautrec ' s defeat brought England openly into the conflict . In late May 1522 , the English ambassador presented Francis with an ultimatum enumerating accusations against France , notably that of supporting the Duke of Albany in Scotland , all of which were denied by the king . Henry VIII and Charles signed the Treaty of Windsor on 16 June 1522 . The treaty outlined a joint English - Imperial attack against France , with each party providing at least 40 , 000 men . Charles agreed to compensate England for the pensions that would be lost because of conflict with France and to pay the past debts that would be forfeit ; to seal the alliance , he also agreed to marry Henry ' s only daughter , Mary . In July , the English attacked Brittany and Picardy from Calais . Francis was unable to raise funds to sustain significant resistance , and the English army burned and looted the countryside . Francis tried a variety of methods to raise money , but concentrated on a lawsuit against Charles III , Duke of Bourbon . The Duke of Bourbon had received the majority of his holdings through his marriage to Suzanne , Duchess of Bourbon , who had died shortly before the start of the war . Louise of Savoy , Suzanne ' s sister and the king ' s mother , insisted that the territories in question should pass to her because of her closer kinship to the deceased . Francis was confident that seizing the disputed lands would improve his own financial position sufficiently to continue the war and began to confiscate portions of them in Louise ' s name . Bourbon , angered by this treatment and increasingly isolated at court , began to make overtures to Charles V to betray the French king . By 1523 , the French situation had entirely collapsed . The death of Doge Antonio Grimani brought Andrea Gritti , a veteran of the War of the League of Cambrai , to power in Venice . He quickly began negotiations with the Emperor and on 29 July concluded the Treaty of Worms , which removed the Republic from the war . Bourbon continued his scheming with Charles , offering to begin a rebellion against Francis in exchange for money and German troops . When Francis , who was aware of the plot , summoned him to Lyon in October , he feigned illness and fled to the Imperial city of Besançon . Enraged , Francis ordered the execution of as many of Bourbon ' s associates as he could capture , but the Duke himself , having rejected a final offer of reconciliation , openly entered the Emperor ' s service . Charles then invaded southern France over the Pyrenees . Lautrec successfully defended Bayonne against the Spanish , but Charles was able to recapture Fuenterrabia in February 1524 . On 18 September 1523 , meanwhile , a massive English army under the Duke of Suffolk advanced into French territory from Calais in conjunction with a Flemish - Imperial force . The French , stretched thin by the Imperial attack , were unable to resist , and Suffolk soon advanced past the Somme , devastating the countryside in his wake and stopping only fifty miles from Paris . When Charles failed to support the English offensive , however , Suffolk — unwilling to risk an attack on the French capital — turned away from Paris on 30 October , returning to Calais by mid - December . Francis now turned his attention to Lombardy . In October 1523 , a French army of 18 , 000 under Bonnivet advanced through the Piedmont to Novara , where it was joined by a similarly sized force of Swiss mercenaries . Prospero Colonna , who had only 9 , 000 men to oppose the French advance , retreated to Milan . Bonnivet , however , overestimated the size of the Imperial army and moved into winter quarters rather than attacking the city ; and the Imperial commanders were able to summon 15 , 000 landsknechts and a large force under Bourbon ' s command by 28 December , when Charles de Lannoy replaced the dying Colonna . Many of the Swiss now abandoned the French army , and Bonnivet began his withdrawal . The French defeat at the Battle of the Sesia , where Bayard was killed while commanding the French rearguard , again demonstrated the power of massed arquebus iers against more traditional troops ; the French army then retreated over the Alps in disarray . D ' Avalos and Bourbon crossed the Alps with nearly 11 , 000 men and invaded Provence in early July 1524 . Sweeping through most of the smaller towns unopposed , Bourbon entered the provincial capital of Aix - en - Provence on 9 August 1524 , taking the title of Count of Provence and pledging his allegiance to Henry VIII in return for the latter ' s support against Francis . By mid - August , Bourbon and d ' Avalos had besieged Marseille , the only stronghold in Provence that remained in French hands . Their assaults on the city failed , however , and when the French army commanded by Francis himself arrived at Avignon at the end of September 1524 , they were forced to retreat back to Italy . Pavia . In mid - October 1524 , Francis himself crossed the Alps and advanced on Milan at the head of an army numbering more than 40 , 000 . Bourbon and d ' Avalos , their troops not yet recovered from the campaign in Provence , were in no position to offer serious resistance . The French army moved in several columns , brushing aside Imperial attempts to hold its advance , but failed to bring the main body of Imperial troops to battle . Nevertheless , Charles de Lannoy , who had concentrated some 16 , 000 men to resist the 33 , 000 French troops closing on Milan , decided that the city could not be defended and withdrew to Lodi on 26 October . Having entered Milan and installed Louis II de la Trémoille as the governor , Francis ( at the urging of Bonnivet and against the advice of his other senior commanders , who favored a more vigorous pursuit of the retreating Lannoy ) advanced on Pavia , where Antonio de Leyva remained with a sizable Imperial garrison . The main mass of French troops arrived at Pavia in the last days of October 1524 . By 2 November , Montmorency had crossed the Ticino River and invested the city from the south , completing its encirclement . Inside were about 9 , 000 men , mainly mercenaries whom Antonio de Leyva was able to pay only by melting the church plate . A period of skirmishing and artillery bombardments followed , and several breaches had been made in the walls by mid - November . On 21 November , Francis attempted an assault on the city through two of the breaches , but was beaten back with heavy casualties ; hampered by rainy weather and a lack of gunpowder , the French decided to wait for the defenders to starve . In early December , a Spanish force commanded by Hugo of Moncada landed near Genoa , intending to interfere in a conflict between pro - Valois and pro - Habsburg factions in the city . Francis dispatched a larger force under Michele Antonio I of Saluzzo to intercept them . Confronted by the more numerous French and left without naval support by the arrival of a pro - Valois fleet commanded by Andrea Doria , the Spanish troops surrendered . Francis then signed a secret agreement with Pope Clement VII , who pledged not to assist Charles in exchange for Francis ' s assistance with the conquest of Naples . Against the advice of his senior commanders , Francis detached a portion of his forces under the Duke of Albany and sent them south to aid the Pope . Lannoy attempted to intercept the expedition near Fiorenzuola , but suffered heavy casualties and was forced to return to Lodi by the intervention of the infamous Black Bands of Giovanni de ' Medici , which had just entered French service . Medici then returned to Pavia with a supply train of gunpowder and shot gathered by the Duke of Ferrara ; but the French position was simultaneously weakened by the departure of nearly 5 , 000 Grisons Swiss mercenaries , who returned to their canton s in order to defend them against marauding landsknechts . In January 1525 , Lannoy was reinforced by the arrival of Georg Frundsberg with 15 , 000 fresh landsknechts and renewed the offensive . D ' Avalos captured the French outpost at San Angelo , cutting the lines of communication between Pavia and Milan , while a separate column of landsknechts advanced on Belgiojoso and , despite being briefly pushed back by a raid led by Medici and Bonnivet , occupied the town . By 2 February , Lannoy was only a few miles from Pavia . Francis had encamped the majority of his forces in the great walled park of Mirabello outside the city walls , placing them between Leyva ' s garrison and the approaching relief army . Skirmishing and sallies by the garrison continued through the month of February . Medici was seriously wounded and withdrew to Piacenza to recuperate , forcing Francis to recall much of the Milan garrison to offset the departure of the Black Band ; but the fighting had little overall effect . On 21 February , the Imperial commanders , running low on supplies and mistakenly believing that the French forces were more numerous than their own , decided to launch an attack on Mirabello Castle in order to save face and demoralize the French sufficiently to ensure a safe withdrawal . In the early morning of 24 February 1525 , Imperial engineers opened breaches in the walls of Mirabello , allowing Lannoy ' s forces to enter the park . At the same time , Leyva sortied from Pavia with what remained of the garrison . In the ensuing four - hour battle , the French heavy cavalry , which had proven so effective against the Swiss at Marignano ten years prior , masked its own artillery by a rapid advance and was surrounded and cut apart by landsknechts and d ' Avalos ' s massed Spanish arquebusiers . Meanwhile , a series of protracted infantry engagements resulted in the rout of the Swiss and French infantry . The French suffered massive casualties , losing the majority of their army . Bonnivet , Jacques de la Palice , La Trémoille , and Richard de la Pole were killed , while Anne de Montmorency , Robert de la Marck , and Francis himself were taken prisoner along with a host of lesser nobles . The night following the battle , Francis gave Lannoy a letter to be delivered to his mother in Paris , in which he related what had befallen him : " To inform you of how the rest of my ill - fortune is proceeding , all is lost to me save honour and life , which is safe . " Soon afterwards , he finally learned that the Duke of Albany had lost the larger part of his army to attrition and desertion , and had returned to France without ever having reached Naples . The broken remnants of the French forces , aside from a small garrison left to hold the Castel Sforzesco in Milan , retreated across the Alps under the nominal command of Charles IV of Alençon , reaching Lyon by March 1525 . Madrid . After Pavia , the fate of the French king , and of France herself , became the subject of furious diplomatic manoeuvring . Charles V , lacking funds to pay for the war , decided to forgo the marriage into the House of Tudor which he had promised Henry VIII and sought instead to marry Isabella of Portugal , who would bring with her a more substantial dowry . Bourbon , meanwhile , plotted with Henry to invade and partition France , and at the same time encouraged d ' Avalos to seize Naples and declare himself King of Italy . Louise of Savoy , who had remained as regent in France during her son ' s absence , attempted to gather troops and funds to defend against an expected invasion of Artois by English troops . She also sent a first French mission to Suleiman the Magnificent requesting assistance , but the mission was lost on its way in Bosnia . In December 1525 a second mission was sent , led by John Frangipani , which managed to reach Constantinople , the Ottoman capital , with secret letters asking for the deliverance of king Francis I and an attack on the Habsburg . Frangipani returned with an answer from Suleiman , on 6 February 1526 , initiating the first steps of a Franco - Ottoman alliance . Suleiman eventually wrote an ultimatum to Charles , asking for the immediate release of Francis — and demanding a yearly tax from the Holy Roman Empire ; when this was not forthcoming , the Ottomans launched an invasion of Hungary in the summer of 1526 , aiming to reach Vienna . Francis , convinced that he would regain his freedom if he could obtain a personal audience with Charles , pressed d ' Avalos and Lannoy , who had intended to transport the king to the Castel Nuovo in Naples , to send him to Spain instead . Concerned by Bourbon ' s scheming , they agreed and Francis arrived in Barcelona on 12 June . Francis was initially held in a villa in Benisanó , near Valencia , but Charles , urged to negotiate a settlement by Montmorency and Lannoy , who suggested that the Italians would soon prove unfaithful to their Imperial alliance , ordered the king brought to Madrid and imprisoned in the citadel there . He adamantly refused , however , to receive Francis personally until the latter had accepted an agreement . Charles demanded not only the surrender of Lombardy , but also of Burgundy and Provence , forcing Francis to argue that French law prevented him from surrendering any lands possessed by the crown without the approval of Parlement , which would not be forthcoming . In September , Francis fell gravely ill , and his sister , Marguerite de Navarre , rode from Paris to join him in Spain . The Imperial doctors examining the king believed that his illness was caused by his sorrow at not being received by the Emperor , and urged Charles to visit him . Charles , against the advice of his Grand Chancellor , Mercurino Gattinara , who argued that seeing Francis on his deathbed was an action motivated by mercenary concerns rather than by compassion , and was thus unworthy of the Emperor , consented ; and Francis soon made a complete recovery . An attempt to escape , however , proved fruitless , and succeeded only in getting Marguerite sent back to France . By the beginning of 1526 , Charles was faced with demands from Venice and the Pope to restore Francesco II Sforza to the throne of the Duchy of Milan , and had become anxious to achieve a settlement with the French before another war began . Francis , having argued to retain Burgundy without result , was prepared to surrender it to achieve his own release . On 14 January 1526 , Charles and Francis agreed to the Treaty of Madrid , by which the French king renounced all his claims in Italy , Flanders , and Artois , surrendered Burgundy to Charles , agreed to send two of his sons to be hostages at the Spanish court , and promised to marry Charles ' sister Eleanor and to restore to Bourbon the territories that had been seized from him . Francis was released on 6 March and , escorted by Lannoy , journeyed north to Fuenterrabia . On 18 March , he crossed the Bidasoa north into France , while at the same time the Dauphin and his brother , who had been brought to Bayonne by Louise and Lautrec , crossed into Spain and into captivity . By this time , Francis had attained peace with England by the Treaty of Hampton Court ; drafted by Thomas Wolsey and the French ambassador at the Hampton Court Palace , the treaty was signed in 1526 , and was ratified by a French delegation in April 1527 at Greenwich . Francis , however , had no intentions of complying with the remaining provisions of the Treaty of Madrid . On 22 March , with the Pope ' s blessing , he proclaimed that he would not be bound by the Treaty of Madrid because it had been signed under duress . Clement VII , who had meanwhile become convinced that the Emperor ' s growing power was a threat to his own position in Italy , sent envoys to Francis and Henry VIII suggesting an alliance against Charles . Henry , having received nothing from the Treaty of Madrid , was receptive to the offers . In May , Francis and the Pope launched the War of the League of Cognac in an attempt to reclaim the territory the French had lost ; Henry , rebuffed in his attempt to have the alliance signed in England , would not join until 1527 . The war would prove unsuccessful ; but Francis and his successor , Henry II , would continue to assert their claims to Milan through the remainder of the Italian Wars , only relinquishing them after the Peace of Cateau - Cambrésis in 1559 .