The safety and potential efficacy of interferon (IFN)-alpha2b were determined for 15 patients during an outbreak of meningoencephalitis due to St. Louis encephalitis (SLE) virus. Clinical and laboratory results were compared with those of 17 untreated patients who were admitted to the same hospital during this nonrandomized preliminary trial. Quadriplegia, quadriparesis, or respiratory insufficiency persisted after the first week of hospitalization, for 11 of 17 untreated patients and for only 2 of 15 treated patients. These complications existed after the second week of hospitalization for 5 of the 17 untreated patients and for 1 of the 15 treated patients. Transient neutropenia and/or mild hepatitis occurred in 11 treated patients. Early initiation of IFN-alpha2b therapy may reduce the severity and duration of complications due to previously untreatable flavivirus meningoencephalitis. A prospective randomized controlled trial is warranted.