Objective:To elucidate the role and prognostic significance of lymphocyte activation-gene-3 (LAG-3) in soft tissue sarcoma (STS). Methods:The expression of LAG-3 in patient and matched normal blood samples was analyzed by flow cytometry. The localization and prognostic values of LAG-3+ cells in 163 STS patients were analyzed by immunohistochemistry. In addition, the expression of tumor-infiltrating CD3+ T, CD4+ T, and CD8+ T cells and their role in the prognosis of STS were evaluated by immunohistochemistry. The effect of LAG-3 blockade was evaluated in an immunocompetent MCA205 fibrosarcoma mouse model. Results:Peripheral CD8+ and CD4+ T cells from STS patients expressed higher levels of LAG-3 than those from healthy donors. LAG-3 expression in STS was significantly associated with a poor clinical outcome (P = 0.038 ) and was correlated with high pathological grade (P < 0.001), advanced tumor stage (P = 0.016). Additionally, LAG-3 expression was highly correlated with CD8+ T-cell infiltration (r = 0.7034,P < 0.001). LAG-3 was expressed in murine tumor-infiltrating lymphocytes, and its blockade decreased tumor growth and enhanced secretion of interferon-gamma by CD8+ and CD4+ T cells. Conclusions:LAG-3 blockade may be a promising strategy to improve the effects of targeted therapy in STS.