Depression has been identified as occurring in the majority of people who commit suicide. Effective antidepressant medications have been available for over half a century. It seems logical to conclude that treatment of depression with antidepressants would have a suicide preventive effect. This has been difficult to demonstrate due to the infrequency of suicide and methodological problems in prospectively testing the hypothesis. Pooled data from controlled clinical trials of antidepressants have not demonstrated a suicide preventive effect, but patient selection and the brief time of most trials limits the power of the data. Some reports from either long-term or very large databases have provided evidence that antidepressants prevent suicide. All but one study using aggregated data from naturalistic settings have shown inverse relationships between use of antidepressants and suicide rates in various populations. Definite conclusions cannot be drawn from naturalistic studies since unknown confounders cannot be excluded. The number of geographically widespread studies reporting positive results with varying methods leads us to conclude, however, that antidepressants do exert a suicide preventive effect.