OBJECTIVE Genetic polymorphisms associated with breast cancer risk are likely to differ among ethnic and molecular subtypes. The ability to identify genetic polymorphisms affecting the risk of estrogen receptor (ER)-positive breast cancer may lead to the more efficient selection of candidates for chemoprevention with endocrine agents. We focused on identifying common genotypes for ER-positive breast cancer in premenopausal Japanese women. METHODS We compared genetic polymorphisms of ERalpha, estrogen metabolism genes (CYP17A1, CYP19A1, HSD17B1 COASY, CYP1B1 and COMT), and p53 between ER-positive and -negative female Japanese breast cancer patients, and analyzed whether these polymorphisms affected the frequency of ER-positive breast cancer. RESULTS Carriers of the G allele of ERalpha (rs6905370) were more frequent in ER-positive breast cancer than in ER-negative breast cancer especially in those under 50-year old. Pairwise analysis showed that combinations of the ERalpha G allele with the homozygous Trp genotype of CYP19A1 codon 39 (rs2236722), the methionine (Met) allele of COMT codon 158 (rs4680) or Pro allele of p53 codon 72 (rs1042522) were more frequent in ER-positive than ER-negative breast cancer, especially in patients less than 50-year old. The frequencies of these combinations were even higher in patients with strongly ER-positive tumors (Allred's scores of 7 or 8). CONCLUSION Our study demonstrated genetic polymorphisms of ERalpha, CYP19A1, COMT and p53 genes frequently occur in ER-positive breast cancer in premenopausal Japanese women.