Since clozapine is, in contrast to conventional neuroleptics, effective in treatment refractory schizophrenic patients its mechanism of action may be different from that of typical neuroleptics. Clozapine has been shown to display the highest binding affinity of all neuroleptics to one of the serotonin (5-hydroxytryptamine, 5HT) receptor subtypes, i.e., the 5HT1c receptor. Furthermore, clozapine, in contrast to conventional neuroleptics, blocks the effect of 5HT agonists on ACTH and corticosterone release in animals. This study hypothesized that clozapine, but not haloperidol would block ACTH and prolactin release induced by the 5HT agonist, m-chlorophenylpiperazine (MCPP). MCPP (0.35 mg/kg PO) was administered after a 3-week drug-free period, after 5 weeks of haloperidol treatment (20 mg/day) and finally after 5 weeks of clozapine treatment (>400 mg/day) in ten male schizophrenic patients. Clozapine, but not haloperidol, blocked the effect of MCPP on ACTH and prolactin release. These results suggest that clozapine, in contrast to haloperidol, is a functional 5HT antagonist. Since MCPP-induced ACTH and prolactin release may be (partially) 5HT1c mediated, these results suggest that clozapine is a potent antagonist at the 5HT1c receptor.