Human CUB and Sushi multiple domains (CSMD1) is considered a crucial role in cancer progression, but the specific function in esophageal squamous cell carcinoma (ESCC) is not clear. Understanding the role of CSMD1 in ESCC progression may lead to a novel strategy for ESCC treatment. Here, we found that both CSMD1 mRNA and protein levels were downregulated in ESCC tissues. Reduced CSMD1 expression was correlated with a poor prognosis in ESCC patients. CSMD1 expression inhibited proliferation, migration and invasion in ESCC cell lines in vitro. CSMD1 deficiency in established xenografted tumors increases tumor size and weight. We further found that CSMD1-overexpression cells are more sensitive to chemotherapy. Moreover, we addressed the role of CSMD1 in the CD8(+) T cell immune response. An in vitro killing assay showed that the cytotoxicity of CD8(+) T cells was inhibited in CSMD1-overexpression tumor cells. In vivo, in CSMD1 deficiency tumor-bearing mice activation and expansion of CD8(+) T cells were increased. Further investigation showed that CSMD1 expression on tumor cells was positively correlated with CD8(+) T cells infiltration and cytokines secretion. These findings highlight that CSMD1 is a tumor suppressor gene in ESCC patients and a positive regulator of CD8(+) T cells expansion and activation, and could increase cytokines secretion, indicating that tumor cell-associated CSMD1 might be a target for ESCC.