To evaluate the effects of physical exercise on breast cancer risk, a large-scale case-referent study of 2376 incident breast cancer cases and 18,977 non-cancer referents was conducted using data from the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC). To adjust appropriately for possible confounders, we examined the effects within subgroups of the study population. The multivariable-adjusted odds ratio (OR) was 0.81 (95% confidence interval (CI): 0.69-0.94) for twice a week or more regular exercise. We observed a decreased risk of breast cancer for women who regularly exercised for health twice a week or more, irrespective of menopausal status, and were able to detect greater risk reductions within particular subgroups, including women who were parous, without a family history or non-drinkers. Among premenopausal women, a particularly strong protective effect of physical exercise was observed (OR=0.57, 95%CI: 0.28-1.15) for those women whose body mass index (BMI) was high (BM > or = 25). In contrast, risk reduction was found (OR=0.71, 95%CI: 0.50-1.01) among postmenopausal women whose BMI was medium (BMI: 22-25). Stratification of history of stomach cancer screening to adjust modifying effects of healthy consciousness allows a more precise assessment of the protective effect of exercise twice a week or more, independent of stomach cancer screening history. This study provides evidence that physical exercise, especially exercise twice a week or more, reduces the risk of breast cancer among Japanese women.