The mechanism(s) by which infectious material is cleared by the host is an area of intensive study. This is especially so with the realization that persistent viral infection is a cause of chronic disease in humans and presents a major health problem. We have used the murine model of infection with lymphocytic choriomeningitis virus to evaluate immune clearance. Mice with a targeted disruption of the IFN-gamma gene mount effective cytotoxic T lymphocyte (CTL) responses after an acute viral challenge and clear virus. CD4+ T cells are not required but CD8+ T cells are mandatory. In contrast, CTL from mice with targeted disruption of the IFN-gamma gene are unable to clear virus from persistently infected mice. In addition to the requirement for IFN-gamma, CD4+ T cells are essential for maintaining a CD8(+)-mediated cure of persistent viral infection.