Family history (FH) is an important indicator of a woman's future risk of developing breast cancer. Using data collected in a large population-based case-control study (6705 cases and 9341 controls), we examined the associations of breast cancer with known risk factors in women reporting a first-degree FH (mother or sister), with an emphasis on lifestyle determinants that may be altered to reduce risk. First-degree FH was reported by 18.4% (n = 1234) of cases and 11.3% (n = 1058) of controls; the overall relative risk (RR) for breast cancer associated with a positive history was 1.70 [95% confidence interval (CI), 1.55-1.87] and 2.34 (95% CI, 1.80-3.02) for breast cancer at age 45 years or younger. Among women with a FH, statistically significant inverse associations were observed for increasing parity (RR per birth = 0.90; P < 0.0001), intake of carotene-rich foods (RR for >2000 IU/day = 0.73; P = 0.02), and strenuous activity as a young adult (RR per episode/week = 0.93; P = 0.02). Recent alcohol consumption increased risk (RR per 13 g/week = 1.21; P = 0.02), as did weight gain during adult life in postmenopausal women (RR per 5 kg = 1.08; P = 0.001). Breast-feeding for any duration was associated with a lower RR in parous, premenopausal women (RR = 0.59; P = 0.04). Associations for most risk factors with breast cancer were similar among women with and without a FH of breast cancer; however, a stronger inverse association was observed for parity in women with a positive history (P for interaction = 0.04). Based on these data, women with a FH may reduce their excess risk of breast cancer through adjustments in lifestyle and reproductive choices. The risk associated with FH of breast cancer seems to be largely independent of other known risk factors.