OBJECTIVE: The study was an investigation of the effect of the antiviral medication valacyclovir on the symptoms of outpatients with persistent schizophrenia. METHOD: Oral valacyclovir, 1 g twice daily, was administered to 65 outpatients over 16 weeks along with their usual psychiatric medications. Changes in psychiatric symptoms were measured with the Positive and Negative Syndrome Scale and were tested for correlations with antibodies to potentially neurotropic human herpesviruses, as measured by immunoassay before the start of the therapy. RESULTS: There was a significant improvement in the psychiatric symptoms of individuals who were seropositive for cytomegalovirus. Improvement was not associated with antibodies to other herpesviruses or to a range of demographic and clinical variables. CONCLUSIONS: The replication of cytomegalovirus may contribute to the symptoms of schizophrenia in some individuals.