BACKGROUND Clozapine is an effective therapy for the treatment of refractory psychosis. Clozapine-associated adverse effects include sedation, weight gain, sialorrhea, palpitations, seizures, and hematologic changes such as agranulocytosis. METHODS We present a four-case series in which clozapine use was associated with either a de novo onset or severe exacerbation of preexisting diabetes mellitus. RESULTS The change in glycemic control was not significantly related to weight gain. Three of the patients have been able to continue on clozapine therapy and have experienced a reduction in psychotic symptoms. CONCLUSIONS Patients with a family history of diabetes mellitus or with preexisting diabetes mellitus may need to have blood sugar monitored closely during initiation of clozapine treatment.