IL-15 and IL-2 possess similar properties, including the ability to induce T cell proliferation. However, whereas IL-2 can promote apoptosis and limit CD8(+) memory T cell survival and proliferation, IL-15 helps maintain a memory CD8(+) T cell population and can inhibit apoptosis. We sought to determine whether IL-15 could enhance the in vivo function of tumor/self-reactive CD8(+) T cells by using a T cell receptor transgenic mouse (pmel-1) whose CD8(+) T cells recognize an epitope derived from the self/melanoma antigen gp100. By removing endogenous IL-15 by using tumor-bearing IL-15 knockout hosts or supplementing IL-15 by means of exogenous administration, as a component of culture media or as a transgene expressed by adoptively transferred T cells, we demonstrate that IL-15 can improve the in vivo antitumor activity of adoptively transferred CD8(+) T cells. These results provide several avenues for improving adoptive immunotherapy of cancer in patients.