Tumors often induce specific CTL responses, but these are usually ineffective at eliminating the growing tumor. The T cell growth factor IL-2 has potential for expanding and prolonging CTL responses, and there is considerable interest in using this cytokine in combination with other immunotherapeutic agents that target T cell responses. Using adoptive transfer of OT-I CD8 T cells specific for OVA257-264 peptide, and E.G7 tumor cells transfected with OVA, we have examined the effects of IL-2 on the generation and maintenance of a CTL response to the tumor. Administration of IL-2 during the initial phase of the response, clonal expansion, and development of effector function, had no effect on the number of CTL generated or the control of tumor growth. In contrast, a short 2-day time course of low-dose IL-2 at the peak of clonal expansion or at later times resulted in prolonged and expanded responses by the OT-I CTL, with concomitant decrease in tumor load and extension of survival. However, when IL-2 administration was more prolonged, as is often the case in clinical trials, the therapeutic benefit was lost due to elimination of the tumor-specific CTL, at least in part through induction of apoptosis. These results demonstrate that use of IL-2 for tumor immunotherapy is very much a double-edged sword and strongly suggest that more limited time and dose regimens may substantially improve its clinical efficacy when it is used in conjunction with approaches that target CTL responses.