Introduction: Obsessive-compulsive (OC) symptoms have been observed in a substantial proportion of schizophrenic patients. There are some reports describing the appearance de novo or reemergence of preexisting OC symptoms under clozapine (CLZ) therapy. However, there are also reports describing a positive effect of CLZ therapy in OC schizophrenic patients. It seems that comorbid OC symptoms are common among CLZ-treated refractory schizophrenic patients and are likely to be an integral part of their illness. The complex nature of the treatment response in this group of schizophrenic patients is as yet unclear. The effects of CLZ on OC symptoms may vary, with evidence of improvement in some and worsening among others. Methods: The present case series study describes our experience with CLZ as a sole agent (n = 10) or in combination with serotonin reuptake inhibitors (n = 5), in schizophrenic patients with prominent OC symptomatology. Results: Systematic analysis of clinical features of our patients, as well as findings in the literature to date, led us to suggest some factors that may predict response to CLZ treatment in treatment-resistant schizophrenic patients with prominent OC symptoms: 1) schizophrenic patients who began to exhibit OC symptoms within the course of the psychotic process need and might to be successfully treated with CLZ alone; 2) when OC symptomatology preceded the development of schizophrenic process, CLZ monotherapy is inefficient and may even worsen OC symptoms; therefore, it should be treated concomitantly with specific anti-obsessive agents; 3) in both groups there is a definite dose-related pro-obsessive influence of CLZ when it is given in high doses. Discussion: Further controlled investigations in a larger cohort of OC schizophrenic patients are needed to substantiate our hypothesis.