Short tandem repeat (STR) polymorphisms in exon 4 of esophageal cancer related gene (ECRG2) have been described to be a risk marker for esophageal carcinoma. The aim of the present study was to examine whether ECRG2 STR polymorphisms are a genetic prognostic marker for esophageal carcinoma. 86 esophageal carcinoma patients that underwent complete surgical resection were included. We retrospectively analyzed peripheral blood samples for STR TCA3/TCA3, TCA3/TCA4 and TCA4/TCA4 in the noncoding region of exon 4 of ECRG2 by using PCR, capillary electrophoresis and DNA sequencing analysis. Associations between STRs and survival were investigated with log-rank test and Cox multivariable analysis. All statistical tests were two-sided. ECRG2 STR TCA3/TCA3 and TCA3/TCA4 genotype were found in 40 (47%) patients respectively, and TCA4/TCA4 was found in 6 (7%) cases. TCA3/TCA3 was statistically significantly associated with reduced tumor-specific, relapse-free and overall survival, compared with grouped TCA3/TCA4 and TCA4/TCA4 genotypes (P<0.05; log-rank test). The median tumor-specific survival of patients with TCA3/TCA3 genotype was 19 months (95% confidence interval [CI] 5 - 33 months) and TCA3/TCA4 and TCA4/TCA4 genotype was 34 months (95% CI: 12 - 55 months). TCA3/TCA3 STR in ECRG2 was statistically the strongest prognostic factor for tumor-specific (relative risk [RR] 2.34 (95% CI 1.31-4.16); p=0.004) and relapse-free survival (RR 2.89, 95% CI 1.63 - 5.11; p<0.001) determined by multivariable Cox regression analysis. STR polymorphism TCA3/TCA3 in exon 4 of ECRG2 is associated with poor clinical outcome in esophageal cancer patients. ECRG2 might play a role in carcinogenesis of esophageal carcinoma and the mechanism has to be explored in future studies.