Negative as well as positive co‐stimulation appears to play an important role in controlling T cell activation. CTLA‐4 has been proposed to negatively regulate T cell responses. CTLA‐4‐deficient mice develop a lymphoproliferative disorder, initiated by the activation and expansion of CD4⁺ T cells. To assess the function of CTLA‐4 on CD8⁺ T cells, CTLA‐4^−/‐ animals were crossed to an MHC class I‐restricted 2C TCR transgenic mouse line. We demonstrate that although the primary T cell responses were similar, the CTLA‐4‐deficient 2C TCR⁺ CD8⁺ T cells displayed a greater proliferative response upon secondary stimulation than the 2C TCR⁺ CD8⁺ T cells from CTLA‐4 wild‐type mice. These results suggest that CTLA‐4 regulates antigen‐specific memory CD8⁺ T cell responses.