Antigenic and costimulatory signals trigger a developmental program by which naive CD8 T cells differentiate into effector and memory cells. However, initial cytokine signals that regulate the generation of effector and memory CD8 T cells are not well understood. In this study, we show that IL-12 priming during in vitro antigenic stimulation results in the significant increase of both primary and memory CD8 T cell population in mice after adoptive transfer of activated cells. The effect of IL-12 priming is closely associated with qualitative changes in CD8 T cells, such as reduced MHC I tetramer binding and CD69 expression, altered distribution of lipid rafts, decreased cytolytic activity, and less susceptibility to apoptosis. Furthermore, exogenous IL-12 priming improved the intrinsic survival properties of memory CD8 T cells, leading to better protective immunity and vaccine-induced memory CD8 T cell responses. However, the experiments with IL-12p40- and IL-12Rβ1-deficient mice showed similar levels of primary and memory CD8 T cell responses compared with wild-type mice, implying that endogenous IL-12 and/or IL-12R signaling in vivo is not critical for CD8 T cell immunity. Together, our results suggest that IL-12 can serve as an important, but dispensable regulatory factor for the development of CD8 T cells, and IL-12 priming could be useful in many medical applications.