Defective-interfering (DI) lymphocytic choriomeningitis virus (LCMV) prevented disease in the central nervous system produced by standard LCMV. Standard LCMV injected into Lewis rats two days after birth produced a disorder distinguishable clinically by weight loss and ataxia and histologically by infiltration of mononuclear cells and necrosis of the cerebellum. Concurrent injection of DI LCMV with standard LCMV prevented the disease and markedly reduced the synthesis of standard LCMV and of viral antigens in the brain. Because inhibition of viral synthesis occurred early (day 3) after infection and because no interferon activity could be demonstrated, it was concluded that the interference effect was likely due to DI virus-mediated homologous interference. Other experiments showed that DI LCMV blocked viral antigen synthesis in culture. The curtailed production of viral antigens and cytolytic standard virus by DI virus may play a role in control of acute and persistent viral infections.