Cytomegalovirus (CMV) encephalitis is well documented in immunosuppressed persons, but its pathogenesis has received little investigative attention. The examination of brain tissue from 2 patients with acquired immunodeficiency syndrome who had CMV encephalitis showed colocalization of CMV inclusions and transforming growth factor (TGF)-β in cells that contained astrocyte-specific glial filaments. To investigate the relationship between CMV and TGF-β in the brain, an ex vivo murine model of CMV-infected astrocytes was established. Cultures of primary murine (strain FVB/N) astrocytes inoculated with murine (Smith strain) CMV expressed, over time, increasing amounts of infectious CMV in parallel with increasing levels of TGF-β mRNA and peptide. Astrocyte release of CMV declined in the presence of antibody to TGF-β and increased substantially after the addition of exogenous TGF-β. These findings suggest that CMV infection of astrocytes induces the production of TGF-β, which in turn enhances productive CMV expression.