It has been proposed that the lack of extrapyramidal side effects of atypical antipsychotic drugs is caused by their fast dissociation or low affinity for the D2 receptor or their concomitant high affinity for other receptors, for example, 5HT2 and D4. We noted that amoxapine, an established antidepressant, has affinity for 5HT2 and D2 receptors, and its effects in preclinical model are very similar to atypical antipsychotics. The objective of this study was to examine the antipsychotic effect and side effect profile of amoxapine versus haloperidol in a double-blind study for 6 weeks in patients with schizophrenia. A total of 54 patients with schizophrenia were titrated to the starting dose of 150 mg/d of amoxapine or 5 mg/d of haloperidol within 3 days. Clinical efficacy and side effects were monitored at baseline, and Weeks 2, 4, and 6.Forty-one patients completed 5 weeks, and 36 patients completed the 6 weeks of follow-up. Both treatment groups showed significant improvement in Positive and Negative Syndrome Scale positive (30%) and total scores (20%), without significant differences between the groups. In addition, in the amoxapine group, significant improvement was seen in the negative symptoms and the Clinical Global Impression. No significant changes were seen on Calgary Depression Scale for Schizophrenia, side effect checklists, and prolactin levels in both groups. The results suggest that amoxapine may be as effective an antipsychotic as haloperidol as predicted by its affinity for D2 and 5HT2 receptors, supporting earlier studies. However, it did not prove to have fewer extrapyramidal side effects than haloperidol, possibly because the baseline scores were very low.