BACKGROUND: There is substantial epidemiological evidence demonstrating that influenza contributes to cardiovascular events in patients who already have cardiovascular diseases. However, the efficacy of influenza vaccination on the prognosis of patients with ischemic heart disease (IHD) is unclear. METHODS: We conducted a systematic search for eligible randomized controlled trials (RCTs) in PubMed, Cochrane, and Embase on September 13, 2024, to investigate the effects of the influenza vaccine on the prognosis of patients with IHD. The effect sizes were combined using random-effects models, and Trial Sequential Analysis (TSA) was used to assess the reliability and validity of the results. RESULTS: Five RCTs with a total of 5659 patients (median age ranging from 57.1 to 66 years, 67.8% male) with IHD were included. The use of influenza vaccine reduced the risk of major adverse cardiovascular events (risk ratio [RR] = 0.67, 95% confidence interval [CI] 0.52-0.87, number-needed-to-treat [NNT] of 37, high certainty), cardiovascular death (RR = 0.55, 95% CI 0.35-0.87, moderate certainty), all-cause mortality (RR = 0.58, 95% CI 0.40-0.84, high certainty) and myocardial infarction (MI) (RR = 0.66, 95% CI 0.46-0.93, high certainty) in patients with IHD compared with control. The analysis revealed no significant benefit regarding hospitalization for heart failure (HF) (RR = 0.91, 95% CI 0.21-3.99, moderate certainty) and revascularization (RR = 0.59, 95% CI 0.10-3.45, moderate certainty). The NNT to avoid 1 event was 37 for major adverse cardiovascular events, 56 for cardiovascular death, 67 for MI, and 41 for all-cause death. TSA showed that the benefit of influenza vaccine in reducing MACE was conclusive, no more trials were necessary. CONCLUSION: This study suggests high level of evidence that the use of influenza vaccine reduce the risk of major adverse cardiovascular events in patients with IHD.