BACKGROUND: Experimental studies in animals have suggested that antidepressants may promote the growth of mammary tumors, but epidemiologic data have not shown consistent associations between antidepressant use and breast cancer. METHODS: We analyzed data from a population-based, case-control study conducted in North Carolina from 1996 to 2000 to examine the association between antidepressant use and breast cancer. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) separately for invasive breast cancer and carcinoma in situ. RESULTS: Over 20% of both cases and controls reported having ever used antidepressants. Overall, women with invasive breast cancer did not report antidepressant use more frequently than controls (OR = 1.0; CI = 0.7-1.2). There was a suggestion that use of selective serotonin reuptake inhibitor antidepressants for 36 months or more was more common among the breast cancer cases (OR = 2.7; CI = 0.9-7.9). Carcinoma in situ cases reported antidepressant use less frequently than controls (OR = 0.6; CI = 0.4-0.8). No consistent relation was observed between duration of use and carcinoma in situ. CONCLUSIONS: Antidepressant use in general was not related to an increased risk of breast cancer. There may be increased risk associated with long-term use of SSRIs. Continued monitoring of this relation is warranted, given the high prevalence of use of these drugs in the general population.