1. Supersensitivity psychosis (SSP) has emerged as a potential side effect of long-term neuroleptic therapy similar to tardive dyskinesia (TD). 2. Six schizophrenic patients with SSP, considered to be drug-resistant, were treated with risperidone, while another 5 were treated with clozapine. 3. The 6 risperidone-treated patients (all women) were rated on the Clinical Global Impression Improvement Scale as at least very much improved. Among the 5 clozapine-treated patients, all 4 men were found to have a marked response to clozapine, while the female patient was judged to be minimally improved. 4. It is hypothesized that not only TD but also SSP arise from destruction of cholinergic interneurons in the striatum as a consequence of prolonged neuroleptic administration. Thus, the drug-induced parkinsonism, which was proposed as mediating the antipsychotic effect of dopamine D2 blocking drugs, depends on the integrity of these cholinergic neurons. If these neurons are destroyed, drugs such as haloperidol lose their therapeutic effect. 5. In contrast, atypical neuroleptics like clozapine and risperidone reduce dopamine release in the striatum independently of prior production of extrapyramidal symptoms and, in this way, may be effective in psychotic illnesses unresponsive to classical anti-D2 neuroleptics. 6. In the present sample of patients, it is worth noting that schizophrenic men were good responders to clozapine. In comparison, risperidone was found to be efficacious in schizophrenic women.