BACKGROUND: Experimental evidence suggests that statins protect against breast carcinogenesis by interrupting cell cycle progression and promoting apoptosis. Evidence in humans is limited and inconsistent. The relation between serum cholesterol levels and breast cancer risk is itself unclear; because cholesterol is the precursor to sex steroid hormones, higher levels could plausibly increase risk. METHODS: The associations of statins, general lipid-lowering drugs, and reported cholesterol levels with breast cancer risk were assessed in the Nurses‘ Health Study, with 6 to 12 years of follow-up. A total of 79,994 women aged 42 to 69 years and free of cancer were followed prospectively for up to 12 years. Current statin use, including duration, was assessed retrospectively in 2000 in 75,828 women. Self-reported serum cholesterol level was assessed prospectively between 1990 and 2000 in 71,921 women. RESULTS: Overall, we documented 3177 incident cases of invasive breast cancer. Compared with nonusers, current lipid-lowering drug users experienced similar breast cancer risk (multivariate relative risk [RR], 0.99; 95% confidence interval [CI], 0.86-1.13). Current use of statins also was not significantly associated with breast cancer risk (RR, 0.91; 95% CI, 0.76-1.08). Associations by duration of current use were similarly null. Self-reported serum cholesterol levels were not associated with breast cancer risk in postmenopausal women with levels of 240 mg/dL or higher (> or = 6.22 mmol/L) compared with less than 180 mg/dL (< 4.66 mmol/L) (RR, 1.04; 95% CI, 0.91-1.17). CONCLUSION: Overall, these data suggest that serum cholesterol levels and the use of lipid-lowering drugs in general and of statins in particular are not substantially associated with breast cancer risk.