Background: Self-poisoning is a common method of suicide and often involves ingestion of antidepressants. Information on the relative toxicity of antidepressants is therefore extremely important. Aims: To assess the relative toxicity of specific tricyclic antidepressants (TCAs), a serotonin and noradrenaline reuptake inhibitor (SNRI), a noradrenergic and specific serotonergic antidepressant (NaSSA), and selective serotonin reuptake inhibitors (SSRIs). Method: Observational study of prescriptions (UK), poisoning deaths involving single antidepressants receiving coroners' verdicts of suicide or undetermined intent (England and Wales) and non-fatal self-poisoning episodes presenting to six general hospitals (in Oxford, Manchester and Derby) between 2000 and 2006. Calculation of fatal toxicity index based on ratio of rates of deaths to prescriptions, and case fatality based on ratio of rates of deaths to non-fatal self-poisonings. Results: Fatal toxicity and case fatality indices provided very similar results (rho for relative ranking of indices 0.99). Case fatality rate ratios showed greater toxicity for TCAs (13.8, 95% CI 13.0-14.7) than the SNRI venlafaxine (2.5, 95% CI 2.0-3.1) and the NaSSA mirtazapine (1.9, 95% CI 1.1-2.9), both of which had greater toxicity than the SSRIs (0.5, 95% CI 0.4-0.7). Within the TCAs, compared with amitriptyline both dosulepin (relative toxicity index 2.7) and doxepin (2.6) were more toxic. Within the SSRIs, citalopram had a higher case fatality than the other SSRIs (1.1, 95% CI 0.8-1.4 v. 0.3, 95% CI 0.2-0.4). Conclusions: There are wide differences in toxicity not only between classes of antidepressants, but also within classes. The findings are relevant to prescribing decisions, especially in individuals at risk, and to regulatory policy.