The immune response against lymphocytic choriomeningitis virus (LCMV) was studied in a mutant mouse strain that does not possess CD8+ T lymphocytes. Virus-specific cytotoxic T cell activity was generated in spleens of wild-type mice in an acute LCMV infection but was not measurable in mutant mice. Injection of replicating LCMV into footpads of wild-type mice induced a CD8+ T cell-mediated swelling that peaked on day 8, followed by a CD4+ T cell-mediated swelling that peaked on day 11, whereas mutant mice exhibited only the CD4+ T cell-mediated swelling. After intracerebral inoculation with LCMV-Armstrong, all wild-type mice died of classical CD8+ T cell-dependent choriomeningitis in 8-10 days. Mutant mice showed symptoms of general malaise but most of them survived. Mutant mice depleted of CD4+ T cells by monoclonal antibody treatment showed no clinical signs of sickness. On day 9 after intravenous infection with LCMV-WE, virus was detected at high titers in spleens and livers of mutant mice but not in those of wild-type mice. On day 70 after injection of LCMV-WE into footpads, virus was not detected in wild-type mice and in one of the three mutant mice tested, but was still measurable in kidneys of the other two mutant mice. These results confirm in a new animal model that CD8+ T cell-mediated immunity is crucial in LCMV clearance and in the immunopathological disease during LCMV infection. In addition, our results demonstrated a less severe form of choriomeningitis mediated by CD4+ T cells and slow clearance of LCMV by alternative pathways independent of CD8+ T cells.