Biologic studies have suggested that antidepressant use may increase breast cancer risk. We conducted a systematic review of trials and controlled epidemiologic studies to assess this association. Pooled data from 31 primary efficacy drug company trials of fluoxetine suggested no increased risk but the short duration of these trials may have been insufficient to detect an association. In one prospective cohort study antidepressant use was associated with breast cancer, but this study was conducted among women attending for breast screening, and only limited data on antidepressant use were available. In a second large prospective drugs screening study no association was found between either amitriptyline or imipramine and breast cancer. In a large well-conducted retrospective cohort study there was no association between antidepressant use and breast cancer. A second retrospective cohort study was flawed, with exposure in those who developed breast cancer being measured over a shorter time period than in those who remained disease free. Two of four case-control studies found no association between antidepressant use and breast cancer after control for a number of potential confounding factors. We conclude that epidemiologic evidence does not support an association between antidepressant use and breast cancer.