The fate of in vivo activated CD8⁺ cytotoxic T cells was studied in transgenic mice expressing a T cell receptor (TCR) specific for the lymphocytic choriomeningitis virus (LCMV) glycoprotein peptide 33‐41 presented by major histocompatibility complex (MHC) class I molecules. LCMV infection of TCR transgenic mice induced LCMV‐specific effector and memory T cells whereas injection of soluble LCMV glycoprotein peptide 33‐41 resulted in tolerance by peripheral deletion and anergy of LCMV‐specific T cells after an initial expansion phase. Similarly, LCMV peptide 33‐41‐specific tolerance could be achieved in normal C57BL/6 mice and was not abrogated by an LCMV infection. These results obtained with a classically MHC‐restricted peptide antigen parallel previous findings with retroviral or bacterial superantigens and indicate a possibility to modulate specifically mature peripheral cytotoxic T lymphocytes in vivo.