CTLA‐4 is a critical negative regulator of T cell responses and CTLA‐4‐deficient (CTLA‐4^–/–) mice die of a lymphproliferative disease. Nevertheless, RAG‐2‐deficient mice reconstituted with a mixture of CTLA‐4^–/– and normal (CTLA‐4^+/+) bone marrow survive in the absence of any signs of disease, although 50% of their T cells do not express CTLA‐4. Using such mixed chimeras, we analyzed the role of CTLA‐4 in specific T cell responses to lymphocytic choriomeningitis virus, Leishmania major and mouse mammary tumor virus, which cause acute, chronic and persistent infections, respectively. The populations of antigen‐specific CTLA‐4^–/–CD4⁺ and CTLA‐4^–/–CD8⁺ T cells became activated, expanded and contracted indistinguishably from CTLA‐4^+/+CD4⁺ and CTLA‐4^+/+CD8⁺ T cells after infection with all three pathogens. Thus, CTLA‐4 is not involved in the down‐regulation of specific T cell responses and peripheral deletion in a T cell‐autonomous fashion.