Cyclooxygenase-2 (COX-2) is involved in carcinogenesis, immune response suppression, apoptosis inhibition, angiogenesis, and tumor cell invasion and metastasis. The gene for COX-2, designated as PTGS2, carries a common polymorphism at position 8473 in the 3'-untranslated region (PTGS2 8473T>C), which has been associated with susceptibility to malignant disease. To investigate the role of this polymorphism for breast cancer, we determined the prevalence of PTGS2 genotypes in 500 women with breast cancer and 500 sex- and age-matched healthy control subjects. Homozygous carriers of the 8473-CC genotype were more frequent among patients (12.4%) than among controls (6.6%; P = 0.002). The odds ratio for carriers of this genotype for breast cancer was 2.1 (95% confidence interval, 1.3-3.3). Among patients, estrogen receptor positivity was less frequent among carriers of a CC genotype (63.9%) than among carriers of a TT or TC genotype (76.9%; P = 0.028). Tumor size, histologic grade, presence of primary lymph node metastases, progesterone receptor positivity, or age at diagnosis were not associated with PTGS2 genotypes. We conclude that the homozygous PTGS2 8473-CC genotype may be associated with breast cancer risk.