On 9 March 1937 the 49th Mixed Brigade had its baptism of fire at the Guadalajara Front, where it became part of the Republican forces that fought the Fascist Italian Corpo Truppe Volontarie. Anti-Fascist Italian Major Arturo Zanoni took the command of the unit relieving de la Macorra for a brief period of time. He was then replaced by Infantry Commander Fulgencio González Gómez who had been captain at the 15th Almansa Regiment "(Regimiento Almansa nº 15)" in Tarragona. The commissar was Francisco Antón Sanz. After the Battle of Guadalajara the unit was sent to the Extremadura front on 14 May. Thereafter it joined the Cuenca Autonomous Group "(Agrupación Autónoma de Cuenca)" and went to the Huesca Front, returning to Madrid shortly after the failed offensive.