Introduction: Influenza virus infection is known to increase the risk of cardiovascular events, especially in populations with pre-existing cardiovascular disease (CVD). Considering that influenza is vaccine preventable, international guidelines recommend high-risk populations with CVD receive an influenza vaccine every year. However, there are various classifications of recommendations and levels of evidence. Previous systematic reviews concluded uncertain evidence on influenza vaccine efficacy for preventing cardiovascular events in the general population or in populations with pre-existing CVD. Limited safety data of influenza vaccines were reported for populations with pre-existing CVD. Randomised controlled trials with larger sample sizes relative to previous studies are emerging, the findings of these trials are likely to be highly influential on summary efficacy estimates.

Methods and analysis: We aim to perform a living systematic review and a prospective meta-analysis to evaluate the efficacy and safety of influenza vaccines compared with no vaccines or placebo for preventing mortality or CVD events in the general population and in populations with pre-existing CVD. Any types of randomised controlled trial and observational study meeting the Population, Intervention, Comparator, Outcome and Study design criteria for the research question will be selected for inclusion. The living systematic review status will be maintained for 3 years with an update for every 6 months. Mainstream medical literature databases will be independently searched by two authors with predefined strategies. Two authors will perform the risk of bias assessment with consensus. Narrative synthesis and meta-analyses will be performed to summarise the results.

Ethics and dissemination: Formal ethical review is not required as this study does not involve primary data collection. We will publish results of the living systematic review and prospective meta-analysis in a peer-reviewed journal. Findings will also be presented at relevant meetings.