Influenza virus infection is associated with significant morbidity and mortality in patients with chronic diseases including heart failure (HF). Annual influenza vaccination is recommended to prevent infection during the winter months. Data regarding its clinical benefit in HF patients are sparse. The purpose of the study was to evaluate the effect of influenza vaccination on clinical outcome in patients with HF. Consecutive patients with HF at a health maintenance organization were evaluated for influenza vaccination status during the winter season of 2017/2018 and its association with cardiac-related hospitalizations and death during 1-year after vaccination. The study cohort included 6,435 HF patients. A total of 4,440 patient were vaccinated during the winter season (69% of the HF cohort). The vast majority (96%) were vaccinated before the winter months (September to November). Patients vaccinated were older patients with more co-morbidities. Cox regression analysis after adjustment for clinically significant predictors demonstrated that vaccination was associated with reduced mortality (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.65 to 0.91, p <0.01) as well as reduced death and cardiovascular hospitalizations (HR 0.83 95% CI 0.76 to 0.90, p <0.001). Adjustment for drug therapy demonstrated a similar result with improved outcome with influenza vaccine. Propensity score matched control analysis demonstrated that vaccination was associated with improved survival (HR 0.80, 95% CI 0.67 to 0.95, p <0.01) and reduced death and cardiovascular hospitalizations (HR 0.86, 95% CI 0.79 to 0.94, p <0.001). In conclusion, Influenza vaccination in patients with HF was associated with improved clinical outcome including improved survival and reduced death and hospitalizations.Copyright © 2020 Elsevier Inc. All rights reserved.