Single nucleotide polymorphisms (SNPs) in energy metabolism related gene may be key agents in the development of human malignancies. In this study, we aimed to examine the association of transcription factor 7-like 2, Leptin (LEP) and LEP receptor (LEPR) polymorphisms with esophageal squamous cell carcinoma (ESCC). A total of 507 ESCC cases and 1,496 controls were enrolled. We found that LEPR rs6588147 AA genotype was associated with ESCC risk (AA vs. GG/GA: adjusted OR=1.90, 95%CI=1.00–3.61, P=0.049). In the stratified analyses, LEPR rs6588147 G>A polymorphism increased the risk of ESCC (<63 years subgroup: AA vs. GG: adjusted OR=2.58, 95%CI=1.00–6.62, P=0.049 and AA vs. GA/GG: adjusted OR=2.71, 95%CI=1.06–6.91, P=0.038; male subgroup: AA vs. GG: adjusted OR=2.19, 95%CI=1.02–4.67, P=0.044 and AA vs. GA/GG: adjusted OR=2.26, 95%CI=1.06–4.80, P=0.035). However, LEP rs7799039 A>G decreased the risk of ESCC (≥63 years subgroup: GG vs. AA: adjusted OR=0.47, 95%CI=0.23–0.95, P=0.035 and GG vs. AA/AG: adjusted OR=0.48, 95%CI=0.24–0.96, P=0.038; BMI≥24 kg/m2 subgroup: AG vs. AA: adjusted OR=0.66, 95%CI=0.45–0.99, P=0.044). In addition, LEPR rs1137101 G>A polymorphism decreased ESCC risk in some subgroups (ever smoking subgroup: GA vs. GG: adjusted OR=0.66, 95%CI=0.44–1.00, P=0.049; ever drinking subgroup: GA vs. GG: adjusted OR=0.54, 95%CI=0.31–0.95, P=0.031 and GA/AA vs. GG: adjusted OR=0.54, 95%CI=0.31–0.93, P=0.027). Our findings suggest that LEPR rs6588147 G>A polymorphism is associated with the increased risk of ESCC; however, LEP rs7799039 A>G and LEPR rs1137101 G>A polymorphisms may be protective factors for ESCC.