In 1975, during the largest epidemic of St Louis encephalitis (SLE) in the United States, 416 cases were diagnosed in Ohio. Persons who were admitted to two Columbus (Ohio) hospitals with suspected acute viral CNS infection were prospectively studied to define the virologic and clinical aspects of SLE. Sixteen cases of SLE were diagnosed serologically. Fifteen patients had signs of encephalitis and one had aseptic meningitis. Six patients had the syndrome of inappropriate antidiuretic hormone secretion. Other frequent findings included moderate peripheral leukocytosis and CSF pleocytosis, with mild elevation of CSF protein levels but normal glucose levels. Severe neurologic sequelae were infrequent. The EEG proved valuable in diagnosis and prognosis. Results of brain scans were normal. Virus in CSF or urine was not demonstrated, nor was viral antigen in CSF or urine sediments. Specific antibody was found in the sera and CSF of all patients who were tested, but interferon was not detected.