Cerebrospinal fluid (CSF) levels of an opioid receptor-active, chromatographically separated endorphin fraction (Fraction I) were measured in 45 schizophrenic patients and 18 healthy volunteers. Significantly increased levels of Fraction I differentiated the patient group from controls, with no difference being found between newly admitted untreated and chronic previously neuroleptic-treated subjects. Fraction I levels did not correlate with age, weight, height, duration of illness, total time hospitalized, or age when symptoms first appeared. No differences were found between patients with or without a family history of schizophrenia. Fraction I levels were negatively correlated with "hallucinations" and "indecision" on the Comprehensive Psychopathological Rating Scale. Increased levels of Fraction I were associated with low levels of the dopamine metabolite homovanillic acid in drug-free schizophrenics. This relationship was not present after neuroleptic treatment or in healthy controls. No relationship was found between Fraction I and the serotonin metabolite 5-hydroxyindoleacetic acid. Neuroleptic treatment did not significantly change Fraction I levels; when only patients above the control range were considered, however, a significant decrease was observed. The data support our previous hypothesis of an increased opioid activity in schizophrenia and further indicate a concomitant dysfunction of brain endorphin and dopamine activity in schizophrenic patients.