We determined the efficacy of in vitro expanded P14 TCR transgenic CD8 T cells to mediate tumor cell elimination and to protect against viral infection in mice. Contrary to previous studies, an adoptive transfer model without lymphodepletion, vaccination or cytokine treatment was used. Antigen-activated P14 T cells cultured in IL-2-containing medium for 7 days (P14IL-2) exhibited potent effector cell functions in vitro but did not confer protection against melanoma growth or viral infection. In contrast, P14 T cells cultured in IL-15 (P14IL-15) were highly effective in vivo although they displayed only moderate effector functions in vitro. Therapeutic efficacy correlated with the survival of the transferred T cells in the recipients: P14IL-2 cells disappeared rapidly whereas P14IL-15 cells persisted for prolonged time. Decreasing the IL-2 concentration in the culture media improved in vivo survival and efficacy but also lowered the cell yield of the cultures. Finally, we could extend the findings with monoclonal P14 T cells to polyclonal CD8 T cells. Thus, in vitro expansion of antigen-specific CD8 T cells in IL-15 allowed the generation of substantial numbers of T cells without inducing terminally differentiated effector cells that turned out to be unfavorable in the transfer model examined here.