To identify immunological predictors of resistance to influenza A infection and illness, the immunological status of live and inactivated virus vaccines subsequently challenged with H1N1 or H3N2 wild-type virus was examined. We refer to prechallenge antibodies of vaccinees receiving live attenuated virus as infection induced and those receiving inactivated virus as inactivated vaccine induced. Inactivated vaccine-induced protection against wild-type virus infection or illness correlated with the level of neuraminidase-inhibiting antibody in serum, local hemagglutinin immunoglobulin G (IgG) (but not IgA) enzyme-linked immunosorbent assay antibody, and hemagglutination-inhibiting antibody in serum. In contrast, infection-induced resistance to wild-type virus infection correlated with local hemagglutinin IgA antibody and neuraminidase-inhibiting antibody in serum, but not with hemagglutination-inhibiting antibody in serum. These observations suggest that live vaccine virus infection-induced and inactivated vaccine-induced immunity may involve different compartments of the immune system; sufficient antibody in either serum or nasal secretions is capable of conferring resistance.