Background Patients with cancer are at increased risk of developing complications of influenza. In this study, the authors assessed the effectiveness of influenza vaccination among cancer patients. Methods A prospective, noninterventional cohort study was conducted during the 2010 to 2011 influenza season. The cohort included adult cancer patients with solid malignancies who were receiving chemotherapy and hematologic patients who had active disease. Patients who died between October and November 2010 (N = 43) were excluded. A comparison was made between patients who received the 2011 seasonal influenza vaccine with those who did not. The primary outcome was a composite of hospitalizations for fever or acute respiratory infections, pneumonia, and/or infection-related chemotherapy interruptions. All-cause mortality was a secondary outcome. A propensity-matched analysis was conducted based on the propensity for vaccination. Results Of 806 patients who were included, 387 (48%) were vaccinated. Factors that were associated independently with vaccination included past influenza vaccination, past pneumococcal vaccination, >6 months since cancer diagnosis, country of birth, and cancer type/status. The primary outcome occurred in 111 of 387 (28.7%) vaccinated patients versus 112 of 419 (26.7%) unvaccinated patients (P =.54). No association was observed between vaccination and the primary outcome in a propensity-matched analysis (N = 436) or during peak influenza activity. The mortality rate was 11.9% (46 of 387 patients) in vaccinated patients versus 19.1% (80 of 419 patients) in unvaccinated patients (P =.005). Vaccination retained a significant association with mortality on multivariable analysis (odds ratio, 2.31; 95% confidence interval, 1.4-3.79) and in a propensity-matched analysis (odds ratio, 2.39; 95% confidence interval, 1.32-4.32). Conclusions Influenza vaccination was associated with lower mortality among cancer patients, although an association with infection-related complications could not be demonstrated. The current Results support efforts to promote influenza vaccination in patients with cancer.