Background: Use of menopausal hormones has correlated with a lower risk of colon cancer in women. Prostate cancer patients (pts) treated with estrogen have a reduced risk of developing GC as a second primary. Several ERβ gene (ESR2) polymorphisms have been associated with colorectal cancer survival (Cancer Res 2013;73:767). To better understand the role of ERβ in relation to GC outcome, we tested whether ESR2 polymorphisms will be associated with overall survival (OS) in GC pts from 2 different regions. Methods: We analyzed genomic DNA extracted from blood or tumor tissues of 169 pts from Japan (64% men, stage IB-IV of AJCC-6^th, median age 67, median follow-up 3.6 years, median survival 5.7 years) and 214 pts from LAC (68% men, stage 0-IV of AJCC-6^th, median age 62, median follow-up 8.2 years, median survival 2.6 years), using PCR-based direct sequencing. ESR2 polymorphisms, which were shown to be of biological significance (rs2978381, rs3020443 and rs1271572), were analyzed for association with OS in both cohorts. Multivariate Cox proportional hazard regression was conducted to test the association after adjustment for age, sex, primary tumor site, stage and other covariates. Results: ESR2 rs1271572and rs3020443 had uni- and multivariate associations with OS in the Japanese but not LAC cohort. Any C allele of ESR2 rs2978381 (T > C)was associated with longer OS than T/T genotype in the Japanese cohort (5-year survival 63 % vs 41 %, p= 0.021) but shorter OS in the LAC cohort (5-year survival 30 % vs 51 %, p= 0.049) although these findings did not remain significant in multivariate analysis. In analysis restricted to distal GC, the ESR2 rs1271572 (C > A) correlated with OS but the effect of A allele was in the opposite direction between the Japanese (n= 121, adjusted HR 2.19, p= 0.019) and LAC cohort (n= 116, unadjusted HR 0.62, p= 0.031). Conclusions: ESR2 polymorphisms have prognostic value in pts with GC. These data also suggest that ERβ pathway may play a key role in tumor progression of GC and its prognostic impact may differ depending on histopathologic, ethnic or epidemiologic differences. Further studies to evaluate the association among different races are warranted.