CSF and sera from 238 newborns and children with various neurological diseases were assayed on bovine cells for the presence of alpha-interferon (IFN). An intrathecal synthesis of pH 2-resistant alpha-IFN was recovered in all newborns and in more than 90% of children with herpes encephalitis. It was also observed in one case of mumps encephalitis and in one case of encephalitis associated with Influenza A infection. An acid-labile alpha-IFN production was detected in CSF from more than one half of patients with viral meningitis or active congenital rubella and in those with neurological complications of systemic lupus erythematosus. This alpha-IFN subtype was also detected in CSF from only 2/37 children with measles encephalitis. In contrast, no alpha-IFN (less than 2 IU) in CSF was found among patients with subacute sclerosing panencephalitis, Guillain-Barré syndrome, Reye's syndrome, acute cerebellar ataxia, infantile spasms or facial paralysis of unknown origin.