IL-2 is a cytokine produced primarily by activated T cells and is thought to be the quintessential T cell growth factor. The precise role of IL-2 in the regulation of CD8 T cell responses to foreign Ag in vivo however remains enigmatic. Using an adoptive transfer system with IL-2-or IL-2R-deficient TCR transgenic CD8 T cells and MHC class I tetramers, we demonstrated that the expansion of antiviral CD8 T cells in secondary lymphoid tissues was IL-2 independent, whereas IL-2 played a more significant role in supporting the continued expansion of these cells within nonlymphoid tissues. Paradoxically, autocrine IL-2 negatively regulated the overall magnitude of the CD8 T cell response in nonlymphoid tissues via a Fas-independent mechanism. Furthermore, autocrine IL-2 did not regulate the contraction or memory phase of the response. These experiments identified a novel role for IL-2 in regulation of antiviral CD8 T cell responses and homeostasis in nonlymphoid tissues.