This study was conducted to determine whether the addition of naltrexone to ongoing neuroleptic treatment would facilitate the reduction in positive or negative symptoms in patients with schizophrenia. Twenty-one patients meeting DSM-III criteria for schizophrenia were enrolled; all patients had been stabilized for at least 2 weeks on their dosage of neuroleptic medicine before entering the study. Patients were randomized to receive either placebo or naltrexone 200 mg/day for 3 weeks in addition to their neuroleptic. Patients randomized initially into the placebo arm were crossed over to receive naltrexone in a single-blind fashion for 3 additional weeks. All patients were rated weekly with the Brief Psychiatric Rating Scale (BPRS). Fifteen patients received placebo and six received naltrexone in the first 3 weeks. No significant effects of naltrexone on total BPRS scores or BPRS subscale scores were observed. Patients who received naltrexone on a single-blind basis at the end of the placebo-controlled trial demonstrated a transient exacerbation in negative symptoms as reflected by the total BPRS score and the BPRS Withdrawal-Retardation subscale score. Repeated-measures analysis of variance (ANOVA) on the BPRS total score of the subsequent treatment with naltrexone showed a trend for a significance in the drug by time effect. Repeated-measures ANOVA on the BPRS Withdrawal-Retardation subscale of the subsequent treatment with naltrexone showed a significant drug by time effect. The current data failed to indicate a clinical benefit when naltrexone was added to the neuroleptic regimen. Other potential applications of naltrexone in schizophrenia are addressed.