BACKGROUND The aim of this study was to examine the efficacy of the combination of fluoxetine plus perphenazine in the treatment of psychotic depression. METHODS Thirty patients who met DSM-III-R criteria for major depression with psychotic features were treated with fluoxetine plus perphenazine for 5 weeks. Patients were assessed at baseline and weekly using the Hamilton Rating Scale for Depression (HAM-D), Brief Psychiatric Rating Scale (BPRS), and a side-effect checklist that included specific extrapyramidal and anticholinergic side effects. RESULTS Twenty-two (73%) of the 30 patients had a 50% or greater reduction in total HAM-D by Week 5. There was a significant improvement in HAM-D and BPRS scores at each week compared with baseline scores. Side effects reported by the patients included dry mouth (40%), blurry vision (40%), constipation (40%), tremor or rigidity (40%), and orthostatic hypotension or dizziness (27%). CONCLUSIONS Fluoxetine when used in combination with perphenazine for the treatment of patients with psychotic depression has a response rate similar to the reported rates of response for tricyclic antidepressants (TCAs) plus antipsychotics, amoxapine, and electroconvulsive therapy. The side effects produced by the fluoxetine plus perphenazine combination were less than what has been reported for TCA plus antipsychotic treatment of psychotic depression and similar to the side effects reported with amoxapine. These data suggest that the combination of fluoxetine and perphenazine is effective for the treatment of psychotic depression and may be easier for patients to tolerate than a TCA plus antipsychotic.