The risk of suicide is a major factor in the morbidity and mortality of schizophrenia, accounting for approximately 10% of deaths in patients with this condition. Indicated risk factors include male gender, social isolation, depression, feelings of hopelessness, a history of suicide attempts, deteriorating health and, uniquely to patients with schizophrenia, young age in men and chronic schizophrenia with numerous exacerbations.There is significant evidence suggesting that clozapine, the gold standard treatment for patients with treatment-resistant schizophrenia, reduces the suicide rate. Although the reasons for this are unknown, beneficial effects of clozapine that are thought to contribute to the reduced suicide rate include improved symptom control, reduced extrapyramidal symptoms, direct antidepressant action, improved cognitive function, and improved compliance. These improve self-perceived quality of life and hence lead to greater desire, and capacity, to survive. Reduced suicide attempts and completed suicide may also reflect the effect of weekly contact with mental health providers to obtain blood for white blood cell monitoring or cohort effects (i.e. time-dependent decrease in suicide attempt rates).Data from a number of studies which have investigated the impact of clozapine on suicide rates in patients with schizophrenia demonstrate that the drug reduces the risk of suicide attempts by approximately 75 to 80%. It had a comparable effect in reducing the completed suicide rate in an epidemiological survey of all US patients in the Clozaril®National Registry.A large scale prospective, randomised study comparing clozapine and olanzapine in patients with a recent history of suicidality is in process. The International Suicide Prevention Trial (InterSePT) will compare the effectiveness of clozapine (300 to 900 mg/day) with olanzapine (10 to 20 mg/day) in reducing suicide and suicide-related events in patients with schizophrenia and schizoaffective disorder. An overview of the study methodology is provided in this review.