Mice with self-limiting P. yoelii or fatal P. berghei infections exhibited a markedly impaired ability to mount specific splenic cytotoxic T-lymphocyte responses to immunization with infectious ectromelia (EV), vaccinia (VAC), or lymphocytic choriomeningitis viruses (LCMV). Lymph node responsiveness, however, was not impaired. Primary CTL responses were depressed in mice immunized 7 days after P. berghei infection, while in P. yoelii-infected mice, depressed responses were detected only during the period corresponding with maximal parasitemia (days 9-12). Secondary VAC-specific CTL responses in vitro by spleen cells of mice previously immunized during P. yoelii infection were also depressed if UV-inactivated rather than infectious VAC was used for immunization. In addition, spleen cells of mice already immune to VAC failed to yield normal secondary CTL responses in vitro during the period of maximal P. yoelii parasitaemia. Collectively, these findings indicate that, during patent malaria infections, priming for and expression of virus-specific CTL responses may be inhibited.