To compare the fatal toxicities of antidepressant drugs in 1987-92. Retrospective epidemiological review of prescription data of the Department of Health, Scottish Office Home and Health Department, and Welsh Health Common Services Authority (excluding data from most private general practices and most hospitals), and mortality data from the Office of Population Censuses and Surveys and General Register Office in Scotland. General practice, England, Scotland, and Wales. Deaths per million prescriptions and deaths per defined daily dose. 81.6% (1310/1606) of deaths from antidepressant overdose were due to two drugs, amitriptyline and dothiepin. The overall average of deaths per million prescriptions was 30.1. The overall rate for tricyclic drugs was 34.14 (95% confidence interval 32.47 to 38.86; P < 0.001), monoamine oxidase inhibitors 13.48 (6.93 to 22.19; P < 0.001), atypical drugs 6.19 (4.04 to 8.80; P < 0.001), and selective serotonin reuptake inhibitors 2.02 (0.64 to 4.17; P < 0.001). The numbers of deaths per million prescriptions of amoxapine, dothiepin, and amitriptyline were significantly higher than expected, while nine drugs had a significantly lower number of deaths per million prescriptions than expected. Analysis of deaths per defined daily dose showed a similar pattern. Safety in overdose should be considered in risk-benefit and cost-benefit considerations of antidepressants. A switch in prescribing, from drugs with a high number of deaths per million prescriptions to drugs with a low number, could reduce the numbers of deaths from overdose. Although this form of suicide prevention can be implemented easily and immediately, its introduction needs to be considered against the higher costs of some of the newer drugs.