ABSTRACT: BACKGROUND:Growing evidence suggested that B- and T-lymphocyte attenuator (BTLA) polymorphisms raised the susceptibility to a wide range of cancers. This study aimed to evaluate whether BTLA variants were related to the risk of esophageal squamous cell carcinoma (ESCC). METHODS:A total of 721 ESCC patients and 1208 matched non-cancer controls were included in this research, and four tagging BTLA polymorphisms (rs2171513 G > A, rs3112270 A > G, rs1982809 G > A, and rs16859629 T > C) were selected and genotyped using SNPscan™ Assays. RESULTS:In the present study, no significant relationship between BTLA polymorphisms and ESCC was observed. However, stratified analyses suggested that the variant of BTLA rs3112270 A > G reduced the risk of ESCC in the male subgroup (AG vs AA: adjusted OR = 0.78, 95% CI = 0.61-0.99, P = .042), BMI < 24 kg/m2 subgroup (AG vs AA: adjusted OR = 0.72, 95% CI = 0.55-0.93, P = .012; AG/GG vs AA: adjusted OR = 0.77, 95% CI = 0.60-0.98, P = .032), and ever drinking subgroup (AG vs AA: adjusted OR = 0.61, 95% CI = 0.38-0.97, P = .037). But when stratified by BMI ? 24 kg/m2 , the rs3112270 A > G polymorphism increased the susceptibility to ESCC (GG vs AA: adjusted OR = 1.91, 95% CI = 1.02-3.59, P = .045). Besides, we demonstrated that BTLA rs2171513 G > A polymorphism was protective of ESCC in the ever drinking subgroup (GA/AA vs GG: adjusted OR = 0.62, 95% CI = 0.39-0.97, P = .037). CONCLUSION:Taken together, our initial investigation postulated that the rs3112270 A > G and rs2171513 G > A variants in the BTLA gene are candidates for the risk of ESCC, which might be helpful for the early diagnosis and treatment of ESCC.