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Background: It is well established that estrogen increases endometrial cancer risk, whereas progesterone opposes the estrogen effects. The PROGINS allele of the progesterone receptor (PGR) gene reduces the function of PGR and has been associated with increased risk of the endometrioid type ovarian cancer. We investigated whether genetic variation in PGR is also associated with endometrial cancer risk using a haplotype-based approach., Methods: We pooled data from two endometrial cancer case-control studies that were nested within two prospective cohorts, the Multiethnic Cohort Study and the California Teachers Study. Seventeen haplotype-tagging single nucleotide polymorphisms (SNPs) across four linkage disequilibrium (LD) blocks spanning the PGR locus were genotyped in 583 incident cases and 1936 control women. Odds ratios (ORs) and 95% confidence intervals (CIs) associated with each haplotype were estimated using conditional logistic regression, stratified by age and ethnicity., Results: Genetic variation in LD block 3 of the PGR locus was associated with endometrial cancer risk (P(global test) = 0.002), with haplotypes 3C, 3D and 3F associated with 31-34% increased risk. Among whites (383 cases/840 controls), genetic variation in all four blocks was associated with increased endometrial cancer risk (P(global test) = 0.010, 0.013, 0.005 and 0.020). Haplotypes containing the PROGINS allele and several haplotypes in blocks 1, 3 and 4 were associated with 34-77% increased risk among whites. SNP analyses for whites suggested that rs608995, partially linked to the PROGINS allele (r(2) = 0.6), was associated with increased risk (OR = 1.30, 95% CI = 1.06-1.59)., Conclusions: Our results suggest that genetic variation in the PGR region is associated with endometrial cancer risk.