Influenza virus with resistance to antiviral drugs emerges with increased frequency in immunocompromised patients and can limit the benefit of M2 and neuraminidase (NA) inhibitors. We document 3 cases of influenza in severely immunocompromised patients from whom virus variants with molecular markers of resistance to anti-influenza drugs were recovered. Virus variants recovered from 2 patients had mutations in the M2, NA (with a previously recognized Glu119Val NA substitution), and hemagglutinin genes. We describe a novel Asp198Asn NA mutation in an influenza B virus and its decreased susceptibility to both oseltamivir and zanamivir.