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Breast cancer is the most common cancer in women. Laboratory studies suggest that antidepressants may promote breast cancer tumor growth. Several epidemiologic studies have evaluated this association with conflicting results.We conducted a cohort study with a secondary nested case-control analysis based on the General Practice Research Database. Our goal was to assess the association between the risk of breast cancer and use of serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and other antidepressants. We calculated adjusted estimates controlling for breast cancer risk factors using unconditional logistic regression.A total of 3708 cases of breast cancer were ascertained. Overall, antidepressant use was not associated with an increased risk of breast cancer. Current users of SSRIs had an odds ratio (OR) of 0.98 (95% confidence interval = 0.81–1.19), whereas current users of TCAs had an OR of 0.86 (0.73–1.00). When only use for longer than 1 year was considered, the corresponding estimates for SSRIs and TCAs were 0.76 (0.53–1.09) and 0.87 (0.70–1.09), respectively. None of the individual drugs was associated with breast cancer risk.Use of antidepressants was not associated with an increased risk of breast cancer regardless of duration of use, daily dose, or specific drug being used. These results, together with evidence from prior studies, support the lack of a clinically meaningful association between breast cancer risk and antidepressants.