BACKGROUND Bisphosphanates are used primarily for the prevention and treatment of osteoporosis, and are also indicated for osseous complications of malignancy. In addition to their bone resorption properties, the most commonly used nitrogen-containing bisphosphonate compounds also inhibit protein prenylation, and thus may exert anti-tumour properties. METHODS To evaluate whether the use of these drugs may be associated with cancer, specifically breast cancer, we conducted a population-based case-control study in Wisconsin from 2003 to 2006. Participants included 2936 incident invasive breast cancer cases and 2975 population controls aged < 70 years. Bisphosphonate use and potential confounders were assessed by interview. RESULTS Using multivariable logistic regression, the odds ratio for breast cancer in current bisphosphonate users compared with non-users was 0.67 (95% confidence interval 0.51-0.89). Increasing duration of use was associated with a greater reduction in risk (P-trend=0.01). Risk reduction was observed in women who were not obese (P-interaction=0.005). CONCLUSIONS These results are suggestive of an additional benefit of the common use of bisphosphonates, in this instance, the reduction in breast cancer risk.