Histaminergic projections innervate brain areas implicated in the pathophysiology of schizophrenia. In a previous open-label study, there was the suggestion that famotidine, and H2 histamine-receptor antagonist, possessed adjuvant therapeutic properties when added to the stable neuroleptic medications regimens of 10 treatment-refractory patients. In that study, the maximal dosage of famotidine was limited to 40 mg/day, the recommended maximal dosage for the treatment of peptic ulcer disease. In this study, we examined 18 patients fulfilling DSM-III-R criteria for schizophrenia and schizoaffective disorder who had famotidine (100 mg/day) added to their stable neuroleptic medication regimen. Patients were rated on baseline, weekly thereafter, and 1 week after famotidine discontinuation, by using the Brief Psychiatric Rating Scale (BPRS), Schedule for the Assessment of Negative Symptoms (SANS), and the Clinical Global Impression (CGI). On all of these outcome measures, statistically significant improvements suggestive of a beneficial adjunctive effect of famotidine were found. Famotidine (100 mg/day) was well tolerated by the study subjects. There was a wide range of famotidine blood levels achieved at the end of 3 weeks of famotidine adjunctive treatment, but these blood levels did not correlate with BPRS or SANS score changes. However, the patients with the greatest improvement in BPRS scores (and without concomitant deterioration in SAND scores) had some of the higher famotidine levels found in the study. Double-blind studies further assessing the potential adjunctive benefit of famotidine in the treatment of schizophrenia are indicated.