p53 is a transcription factor for Waf-1/p21, a cyclin-dependent kinase inhibitor. Certain polymorphic variants of Waf-1 and p53 have been evaluated for their association with cancer risk. Previous studies indicated that certain p53 polymorphisms confer an increased risk of breast cancer [odds ratios (ORs) and 95% confidence intervals (CIs) = 2.9, 1.4-6.3 Carcinogenesis (Lond.), 17: 1313, 1996; 2.5, 1.3-4.8 Cancer Epidemiol. Biomark. Prev., 6: 105, 1997; and 1.5, 1.1-2.0, Anticancer Res., 18: 2095, 1998). The primary objectives of this study were to test the hypotheses that the serine variant (codon 31 polymorphism) of Waf-1 is also involved in this process and that there is an interaction between Waf-1 and p53 polymorphisms. To do this, Waf-1 and p53 genotypes were determined for women enrolled in a breast cancer case-control study (Caucasians, African-Americans and Latinas; 487 Waf-1 and 504 p53 genotypes were obtained). Multivariate logistic regression was used to evaluate possible associations between Waf-1 and p53 polymorphisms, race, and menopause. The primary aim was to determine whether an interaction between Waf-1 and p53(1-2-1) existed. Whereas multivariate analysis suggested associations between breast cancer and inheritance of Waf-1(ser31) in African-Americans (OR, 2.32; 95% CI = 0.66-5.60; n = 37 cases and 65 controls) and Latinas (OR, 2.22; 95% CI = 0.71-6.89; n = 30 cases and 75 controls), and inheritance of p53(1-2-1) in Caucasians (OR, 3.15; 95% CI = 1.14-8.89; n = 93 cases and 187 controls), we did not see an interaction between Waf-1(ser31) and p53(1-2-1). Consistent with the finding that p53(1-2-1) is a risk factor for Caucasian women was the observation of a strong interaction between race and p53 (P < 0.01).