Prolonged exposure to combined hormone replacement therapy (estrogen plus progestin) increases a woman's risk of breast cancer, whereas estrogen-only hormone replacement therapy does not. This suggests that progesterone may play a role in breast carcinogenesis. Association studies have reported inconsistent relationships between progesterone receptor gene variants and breast cancer. A population-based case-control study in three counties of the Philadelphia Metropolitan area was undertaken. We evaluated 8 PGR candidate SNPs and 18 PGR tagging SNPS in 487 breast cancer cases and 843 controls using multivariable logistic regression with adjustment for combined hormone replacement therapy use. Separate analyses were conducted for European Americans (EA: 399 cases, 490 controls) and African Americans (AA: 88 cases, 353 controls). In EAs, no significant associations were observed with the investigated PGR variants. In AAs, two tagging SNPs (rs590688 and rs10895054) were statistically significantly associated with breast cancer. For rs590688, each addition of the C allele was protective compared to the G allele (OR = 0.56, 95 % CI 0.39-0.82, p value 0.003, corrected p value 0.03). For rs10895054, each addition of the T allele increased the risk of breast cancer compared to the A allele nearly threefold (OR = 2.9, 95 % CI 1.47-6.02, p value 0.002, corrected p value 0.04). Three haplotype blocks, all containing rs590688, were found to be significantly associated with breast cancer risk. Environmental exposures, namely parity and obesity modified the effect of both SNPs on breast cancer risk in EA. This is the first study to find an association between two PGR variants and breast cancer in AA women. These results suggest that studies of PGR variants in other non-White populations may reveal additional cancer associations of interest.