Background: Deaths from antidepressants continue to account for a substantial proportion of drug-related deaths. Aims: To investigate the relative toxicity of the major classes of antidepressant drugs, with the specific objective of assessing this in relation to the cause of death; and to analyse the deaths where there were multiple mentions of antidepressant drugs or other psychoactive drugs with antidepressants. Method: Mortality data were collected from the National Programme of Substance Abuse Deaths, and antidepressant prescription data were collected. Results: Most deaths from antidepressant drugs were suicides (80%). Tricyclic antidepressants (TCAs) accounted for more drug mentions than did other antidepressant drugs (12 per million prescriptions). Selective serotonin reuptake inhibitors (SSRIs) were associated with a significantly lower risk of toxicity, but 93% of deaths from SSRIs occurred in combination with other drugs, especiallyTCAs (24.5%). In 'combination' deaths patients were significantly more likely to have had a history of drug misuse. Conclusions: The efficacy and safety of augmentation therapy with TCAs in SSRI-resistant patients should be monitored carefully, and patients prescribed antidepressants should be screened for drug use/misuse.