Viral infections often induce robust T cell responses that are long-lived and protective. However, it is unclear to what degree systemic versus mucosal infection influences the generation of effector and memory T cells. In this study, we characterized memory CD8(+) T cells generated after respiratory influenza virus infection and compared the phenotypic and functional qualities of these cells with memory T cells generated after systemic infection with lymphocytic choriomeningitis virus (LCMV). Using a recombinant influenza virus expressing the LCMV gp(33-41) epitope and TCR transgenic CD8(+) T cells with a fixed TCR, we compared responses to the same Ag delivered by mucosal or systemic viral infection. Memory cells generated postinfection with either virus showed only a few phenotypic differences. Yet, influenza memory T cells produced lower amounts of effector cytokines upon restimulation and displayed reduced proliferation compared with LCMV-induced memory cells. Strikingly, we observed reduced expansion of spleen- and, in particular, lung-derived influenza memory cells after recall in vivo, which correlated with reduced early protection from secondary infection. These findings suggest that qualitatively different memory CD8(+) T cells are generated after respiratory or systemic virus infections.