Influenza A and B viruses cause serious, sometimes fatal, disease in immunocompromised patients, particularly bone marrow and solid organ transplant recipients. Protracted disease has also been recognized in certain oncology and HIV-infected patients. Currently available inactivated vaccines are variably immunogenic in such groups. Poor humoral immune responses are seen within 2 years of bone marrow transplantation, often following solid organ transplantation, and commonly in patients with advanced HIV infection. Oral amantadine and rimantadine are useful for prophylaxis and treatment of influenza A virus infections, but their efficacy, particularly in treatment of severe disease, has not been rigorously established in immunocompromised hosts. Case reports document the emergence of drug-resistant variants and prolonged viral shedding in some patients. Aerosol and intravenous ribavirin has been used to treat severe influenza in small numbers of immunosuppressed patients, but the efficacy of ribavirin by either route has not been established in such patients. The neuraminidase inhibitor GG167 is active in experimental influenza but requires topical application to the respiratory tract and has had limited clinical study in natural influenza. More effective interventions for serious influenza infections will likely require combinations of antiviral drugs.