Acute infection of immunocompetent mice by lymphocytic choriomeningitis virus induces a potent cytotoxic T-lymphocyte response that eliminates infectious virus. Concurrently and paradoxically, there is a general suppression of lymphocyte responses to mitogens and to other infectious agents. Splenocytes from infected mice released significant amounts of gamma interferon in response to mitogenic stimulation in vitro, but neither interleukin 2 nor interleukin 4 was similarly elevated relative to the amounts released by control cells. Early T-cell receptor-proximal signaling events were found to be intact, confirming that the cells were viable and had received the mitogenic stimuli in an appropriate manner. Acutely infected adult thymectomized mice regained concanavalin A responsiveness in parallel with euthymic mice, if T cells were left unmanipulated for several weeks after clearance of virus from the mice. Therefore, although acute lymphocytic choriomeningitis virus infection has the effect of disrupting proliferation when the T-cell receptor is ligated, this state is only temporary. In contrast, T cells from persistently infected adult mice reveal long-lasting alterations in concanavalin A responsiveness.