Depression and antidepressant use is highly prevalent among U.S. women and may be related to increased breast cancer risk. However, prior studies are not in agreement regarding an increase in risk. We conducted a prospective cohort study within the Nurses' Health Study (NHS) and NHSII among females age 25 and older. Over more than 10 years of follow-up in each cohort, 4,014 incident invasive breast cancers were diagnosed. We used Cox proportional hazards regressions with updating of exposures and covariates throughout follow-up to estimate HRs and 95% confidence intervals (CIs) for associations between clinical depression and antidepressant use with invasive breast cancer risk. Analyses were repeated separately for disease, as well as stratified by estrogen receptor (ER) subtype and menopausal status at diagnosis. No statistically significant associations were observed between clinical depression (HR for reporting ≥3 times vs. 0, 1.13; 95% CI, 0.85-1.49) or antidepressant use (HR for reporting ≥3 times vs. 0, 0.92; 95% CI, 0.80-1.05) and invasive breast cancer risk in multivariable analyses. Likewise, we observed no significant associations between clinical depression or antidepressant use and risk of , ER, ER, premenopausal, or postmenopausal breast cancer. In the largest prospective study to date, we find no evidence that either depression or antidepressant use increase risk of breast cancer. The results of this study are reassuring in that neither depression nor antidepressant use appear to be related to subsequent breast cancer risk. .