A smallpox vaccination program has been initiated. The vaccine is a live virus that was used in the last century. Postvaccinal encephalitis is a complication of this vaccine. The clinical presentation, course, neuroimaging findings, and spinal fluid abnormalities are similar to a disorder that physicians are familiar with, acute disseminated encephalomyelitis. This complication can be prevented with the administration of antivaccinia gamma globulin at the time of vaccination. Antivaccinia gamma globulin is not efficacious once this complication occurs. Intravenous methylprednisolone is the recommended therapy, although intravenous immunoglobulin and plasmapheresis should be investigated in the treatment of postvaccinal encephalitis.