A promising approach toward preventing and treating autoimmune disease involves identifying the mediating antigen and then tolerizing the autoreactive T cells with the corresponding antigen. For success, this method will require the specific tolerization of active helper or CTL responses while maintaining the integrity of the immune system. In this report, we selectively eliminated an ongoing CTL response by administering soluble peptide. BALB/c mice were immunized with two H-2Kd-restricted immunodominant CTL epitopes derived from HIV and malaria together with a T helper epitope to elicit a strong CTL response. Beginning 3 days later, mice were injected 3 times at 3-day intervals with 500 micrograms of only one or both of these epitopes in PBS. Following these injections, only one of two active CTL responses was tolerized without affecting T helper cells. This tolerization state requires antigen for its maintenance, may be retolerized upon return, and is not due to active or antigen-driven bystander suppression. This study suggests that soluble peptides may be utilized to treat or prevent autoimmune diseases caused by autoreactive CTLs.