We sought to determine if specific dietary antioxidants may be particularly effective in reducing breast cancer risk for women reporting family history (FH) of breast cancer in a first-degree relative. Interviews regarding usual diet, health, and family histories were conducted with 262 premenopausal and 371 postmenopausal women with incident, primary breast cancer from western New York (United States). These women were frequency-matched by age and county of residence with community controls. Among premenopausal women, there was a significant interaction between FH and alpha-tocopherol; alpha-tocopherol was associated with significantly decreased risk among FH+ women (adjusted fourth-quartile odds ratio [OR] = 0.01, 95 percent confidence interval [CI] = 0.0-0.3). This association was much weaker for FH- women [OR = 0.7, CI = 0.4-1.2]. For FH- women, a significant inverse association was observed between beta-carotene and premenopausal breast-cancer risk (OR = 0.4, CI = 0.3-0.5), but not for FH+ women (OR = 0.5, CI = 0.1-4.0). Similar relationships, although not as strong, were noted among postmenopausal women. Although limited by small numbers, these results suggest that biologic mechanisms of tumorigenesis may differ in FH+ and FH- women, and that alpha-tocopherol may be a potential chemopreventive agent for women with a family history of breast cancer, particularly premenopausal women.