Recent studies indicate that innate immunity in influenza virus infection is an area of substantial importance for our understanding of influenza virus pathogenesis, yet our knowledge of the mechanisms controlling innate immunity remains limited. Further delineation of the roles of NK cells and innate immunity in viral infection may have important implications for the development of improved influenza virus vaccines. In this study, we evaluated the phenotype and function of NK and T lymphocytes, as well as influenza virus-specific immunoglobulin G production, prior to and following vaccination with the routinely administered trivalent influenza virus vaccine. We demonstrate influenza virus antigen-specific innate and adaptive cellular responses and evaluate changes in NK cell receptor expression over time. Our results demonstrate increased innate and adaptive cellular immune responses and show that NK cells are a significant source of gamma interferon (IFN-gamma) following influenza virus vaccination. An increase in the frequency of IFN-gamma-producing NK cells was observed in many subjects postvaccination. The subset distribution with respect to CD56(dim) and CD56(bright) NK cell subsets remained stable, as did the NK cell phenotype with respect to expression of cell surface activating and inhibitory receptors. These results may form the basis for further investigations of the role of NK cells in immunity to influenza.