One of the highest risk of esophageal squamous cell carcinoma (ESCC) in the world has been reported in Iran, which is located in the Asian esophageal cancer belt. ESCC constitutes 90% of the esophageal cancer cases in Iran. Genome wide association studies (GWASs) in Chinese have identified a number of candidate variants, of which PLCE1rs2274223, C20orf54rs13042395 and RUNX1rs2014300 are studied in high risk populations including Chinese, Caucasians and Africans. However, results are inconsistent and it is unknown whether similar associations exist in Iranian population. We evaluated association of three GWAS identified variants with risk of ESCC in an Iranian cohort consisted of 200 ESCC patients and 300 healthy controls and conducted meta-analysis of ESCC risk associated with rs2274223 (involving 9810 cases and 13,128 controls) and rs13042395 (involving 2363 cases and 5329 controls). Logistic regression analysis showed that rs2274223 was associated with ESCC under codominant [GG/AA, 2.47(1.17-5.23), P:0.021], dominant [AG + GG/AA, 1.57(1.09-2.27), P:0.016], recessive [GG/AA+AG, 2.18(1.04-4.56), P:0.036] and log-additive models [1.51(1.12-2.02), P:0.006]. C20orf54 rs13042395 was not associated with ESCC under any genetic model. RUNX1 rs2014300 was associated with risk of ESCC assuming codominant [AG/GG, 0.63(0.41-0.97), P:0.018], dominant [AG + AA/GG, 0.59 (0.39-0.89), P:0.010] and log-additive models [0.61 (0.42-0.87), P: 0.005]. Meta-analysis found significant associations between rs2274223 and ESCC under all analyzed genetic models. However, meta-analysis stratified by ethnicity showed a significant association in Asians but not non-Asian populations. No significant association was found for rs13042395 in meta-analysis. This study provided first evidence for association of GWAS-identified variants with risk of ESCC in an Iranian cohort.