The capacity of a mouse-adapted strain of canine distemper virus (CDV) to induce central nervous system (CNS) disease in weanling mice was investigated. Lethality of infection was found to be mouse-strain-dependent. In sensitive strains, an acute meningoencephalomyelitis developed. Brain tissue from acutely ill animals demonstrated numerous foci of viral antigen, and extracts yielded infectious virus. Mice of resistant strains, notably the SJL strain, survived the effects of acute infection, appeared well for several weeks, and then began to develop signs of subacute CNS disease. Preliminary histopathologic examination of brain and cord from acutely ill animals revealed prominent perivascular mononuclear cell infiltrates, mononuclear cell meningitis, and gliosis. These features were also found in the subacute disease, where, however, the lesions were less severe. Also, in the latter, virus antigen could not be demonstrated. The results indicate that CDV infection of mice may provide a promising model system for the study of virus-induced chronic CNS disease.