Cytotoxic CD8(+) T cells are key mediators of viral clearance during primary infection through their production of IFN-gamma and lysis of virally infected cells. Comparatively, the cytokines IL-4 and IL-13 are typically associated with the development of Th2 immune responses against allergens and parasites, while their influence on cytotoxic CD8(+) T cell responses is controversial. We have investigated the roles of IL-4 and IL-13 in the development of CD8(+) T cell responses against influenza infection. We show that in the absence of either IL-4 or IL-13, CD8(+) T cells proliferated and a normal secondary cytotoxic response developed in vitro. In striking contrast, the absence of IL-4Ralpha resulted in impaired ex vivo proliferation and consequently no secondary CTL activity, whereas the in vivo response appeared normal. We show that the presence of CD4(+) T cell help, or the addition of exogenous IL-2 in vitro, restored the response. Taken together, this work reveals previously unrecognized in vivo redundancies between IL-4, IL-13 and IL-2 during immune responses against influenza virus.