Many national guidelines recommend annual influenza vaccination of immunocompromised patients, although the decision to vaccinate is usually at clinical discretion. We conducted a systematic review and meta-analyses to assess the evidence for influenza vaccination in this group, and we report our results by etiology. Meta-analyses showed significantly lower odds of influenza-like illness after vaccination in patients with human immunodeficiency virus (HIV) infection, patients with cancer, and transplant recipients and of laboratory-confirmed influenza in HIV-positive patients, compared with patients receiving placebo or no vaccination. Pooled odds of seroconversion and seroprotection were typically lower in HIV-positive patients, patients with cancer, and transplant recipients, compared with immunocompetent controls. Vaccination was generally well tolerated, with variation in mild adverse events between etiological groups. Limited evidence of a transient increase in viremia and a decrease in the percentage of CD4(+) cells in HIV-positive patients was found although not accompanied by worsening of clinical symptoms. Clinical judgment remains important when discussing the benefits and safety profile with immunocompromised patients.