- Objectives Clotiapine is a classic neuroleptic with a chemical structure similar to clozapine. It was said that patients unresponsive to other neuroleptics respond to clotiapine although it causes extrapyramidal syndromes (EPS) like other typical neuroleptics. We conducted a study of clotiapine vs. chlorpromazine in severe chronic active psychotic hospitalized schizophrenia patients. Methods The design was double-blind crossover of clotiapine vs chlorpromazine. No washout was necessary from previous neuroleptic treatment, and flexible overlap with the study medication was individualized for each patient. Patients were treated after reaching neuroleptic monotherapy for 3 months with clotiapine and 3 months with chlorpromazine, in random order. Medication was supplied in identical capsules of 100 mg chlorpromazine or 40 mg of clotiapine. Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) were rated every 2 weeks and Nurse's Observation Scale for Inpatient Evaluation (NOSIE) every month. Results Fifty-eight patients were randomized. Forty-three patients completed at least one phase of the study, and thirty-three completed both phases. Because of the small number of hostel patients and the very high dropout rate in the hostel patients, data analysis was done separately for inpatients and hostel patients. Clotiapine was significantly superior to chlorpromazine in 26 inpatients completing the crossover, on the PANSS, NOSIE and CGI. Clotiapine was also superior to chlorpromazine in an analysis of the parallel inpatient groups in the first three months before the crossover. Conclusion Some classic neuroleptic compounds may have superiority to chlorpromazine in a "clozapine-like" manner, despite a typical profile for EPS.