Background The codon 72 polymorphism in the p53 gene relates to the risk of breast cancer (BC), but this relationship in racially diverse populations is not known. The present study examined the prognostic value of this polymorphism for African American (AA) and Caucasian (CA) BC patients separately and considered the confounding variables of molecular subtypes and somatic mutations in p53. Methods Tissue sections of BCs from 116 AAs and 160 CAs were evaluated for p53 mutations and genotyped for the codon 72 polymorphism. The relationships of phenotypes to clinicopathologic features were determined by χ2 analyses; patient survival was estimated by Kaplan-Meier univariate and Cox regression multivariate models in a retrospective cohort study design. Results The proportion of single nucleotide polymorphism (SNP) 72 alleles differed for races. Many cancers of AAs were Pro/Pro, but most for CAs were Arg/Arg. A higher frequency of missense p53 mutations was evident for AAs. There was an interaction between the SNP allele and p53 mutations for AA women only. The proportion of women with both the Pro/Pro allele and a p53 somatic mutation was higher for AA than CA women. The interaction between missense p53 mutations and Pro/Pro had a negative effect on survival, particularly for AAs with luminal cancers. Conclusions For BCs, the survival effect of SNP72 combined with a p53 missense mutation is dependent on race and molecular subtype. Although such a mutation is a marker of poor prognosis, it is relevant to identify the variant Pro/Pro in the case of AAs, especially those with luminal subtypes of BC.