Although not universally accepted, evidence exists that clozapine treatment may be associated with neuroleptic malignant syndrome (NMS). To date, 10 cases of NMS associated with the use of clozapine have been reported in the literature. We report two more cases of NMS in patients on clozapine treatment and review the clinical presentations, biochemical features, risk factors, treatment, and rechallenge with neuroleptics in all reported patients who developed NMS while receiving clozapine treatment. An update and critical review of clozapine-induced NMS are also presented. Clozapine treatment can cause NMS similar to that induced by conventional neuroleptics. A history of NMS, existing brain insults, low serum iron concentrations, and being a young male may be risk factors for the development of NMS associated with clozapine treatment. NMS most commonly occurs when clozapine is being used along with other psychotropics. Early recognition of the syndrome and cessation of clozapine when NMS occurs are advised. Supportive care and use of dopamine agonists and dantrolene may be helpful in treating clozapine-associated NMS. These results support the notion that clozapine can cause NMS. However, NMS associated with clozapine treatment is a rare event. When it happens, the clinical presentation, risk factors, and management appear to be similar to those of NMS associated with conventional neuroleptics.