A randomized controlled trial of influenza vaccine to prevent adverse vascular events. Cardiovascular disease is a leading cause of death globally estimated to be responsible for approximately 17 million deaths annually. Heart disease and stroke account for nearly one third of all deaths and are a major cause of hospitalization. Patients with congestive heart failure (CHF) are at particularly high risk. Clinical trials demonstrate that nearly one third of patients with CHF will experience a myocardial infarction (MI), stroke, or hospitalization for CHF. Observational studies have established an association between influenza infection and major adverse vascular events . It follows that vaccinating such a high risk group as patients with CHF against influenza may prevent adverse vascular events. However, these studies are subject to bias and a well designed clinical trial is needed to test the effect of influenza vaccination on preventing adverse vascular events. The goal of this study is to assess whether inactivated influenza vaccine can reduce adverse vascular events in high risk participants. We will address the question by randomizing patients at high risk for adverse vascular events to either annual inactivated influenza vaccine or to placebo over three influenza seasons. The primary outcome is a composite of cardiovascular (CV) death, non-fatal myocardial infarction (MI), non- fatal stroke, and hospitalization for CHF.  We will enroll 3,500 participants from centres in seven countries: Philippines (the lead centre), Mozambique, Sudan, Uganda, Saudi Arabia, Malaysia, China. This proposed randomized trial has important implications for the management of patients at high risk for major adverse vascular events. Although the influenza vaccine is recommended annually for groups with diabetes and cardiovascular disease in many counties, uptake of these recommendations is relatively low. Cardiologists in most jurisdictions do not routinely recommend annual influenza vaccine for their patients as a strategy to reduce future adverse vascular events such as acute coronary syndrome or stroke. Uptake of influenza vaccine in patients with heart disease varies by country but in INTER-CHF sites (where are trial will be conducted) is 11% on average. Rigorous demonstration of influenza vaccine leading to a reduction in major adverse vascular events would represent a landmark study. We anticipate that such a trial would influence management decisions by physicians for patients at high risk for major vascular events. The effect size we propose testing is comparable to secondary prevention strategies available and given the fact that a vaccine is given once annually it is simple and inexpensive. Given the large burden of disease, the possibility to reduce cardiovascular and stroke related death is a compelling argument for this trial.  If influenza vaccine is shown to reduce adverse vascular events, it will represent an important change in how prevention of adverse vascular events is thought about. The fact that our primary outcome is a composite, including various forms of vascular disease will increase generalizability. The study would be a milestone in contributing to evidence-based clinical as well public health policy. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.