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Background: We aimed to characterize the relationships of lymphocyte activation gene-3 (LAG-3) expression, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) expression, and CD8 + tumor-infiltrating lymphocyte (TIL) density, and to investigate the joint prognostic impact of these three markers in patients with surgically resected esophageal squamous cell carcinoma (ESCC)., Methods: Expression of LAG-3, CTLA-4 and the density of CD8 + TILs were evaluated by immunohistochemistry in resected ESCC. The associations between LAG-3 expression and clinicopathologic characteristics, as well as patient prognoses, were analyzed., Results: A total of 183 patients were included. LAG-3 expression was observed in 69 (37.7%) patients. Positive LAG-3 expression was significantly associated with CTLA-4 expression (P=0.004). LAG-3 positivity, CTLA-4 positivity, and low CD8 + TIL densities were significantly associated with worsening recurrence-free survival (RFS) [LAG-3: hazard ratio (HR), 1.72; 95% confidence interval (CI), 1.10-2.89; P=0.019; CTLA-4: HR, 1.69; 95% CI, 1.04-2.73; P=0.033; CD8 + : HR, 0.60; 95% CI, 0.38-0.94; P=0.025] and overall survival (OS) (LAG-3: HR, 2.09; 95% CI, 1.24-3.53; P=0.006; CTLA-4: HR, 1.47; 95% CI, 0.86-2.53; P=0.161; CD8 + : HR, 0.56; 95% CI, 0.33-0.95; P=0.032). Subgroup analysis revealed that the LAG-3 CTLA-4 CD8 + group had the best RFS (P<0.001) and OS (P<0.001)., Conclusions: LAG-3 expression was correlated with CTLA-4 expression on TILs. Positive LAG-3 expression was associated with poor prognoses in ESCC. A combination of LAG-3, CTLA-4 expression and CD8 + TILs density could further stratify patients into different subgroups with distinct prognoses., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)