A double-blind placebo-controlled cross-over investigation of the possible antipsychotic action of [des-Tyr1]-gamma-endorphin (DT gamma E) was undertaken in schizophrenic patients. This non-opiod derivative of gamma-endorphin has recently been shown to exert both neuroleptic-like effects in animals and an antipsychotic action in schizophrenic patients failing to respond to conventional neuroleptic therapy. 13 patients undergoing continuous neuroleptic therapy, and suffering from either chronic or acute, frequently-relapsing schizophrenia and displaying persistent productive symptoms (hallucinations, acute delusions) were selected for the trial. After one day of single-blind injection of placebo, two successive double-blind treatment periods of 4 days each followed, viz 4 days with i.m. injections of 2 mg DT gamma E preceding 4 days of placebo injections or vice versa. Psychopathological evaluation was performed twice daily by use of the IMPS and an eight-point-scale appropriate for the estimation of special target symptoms (VBS). The mean data obtained from the whole sample of 13 patients show that placebo and DT gamma E produce a reduction in symptomatology of an appoximately equal magnitude. The results provide no support for the hypothesis of an antipsychotic efficacy of DT gamma E in the treatment of chronic schizophrenic patients. In the subgroup of acute cases, however, a therapeutic action of DT gamma E appears possible