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Objective: To investigate the potential association of 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) expression with the prognosis of patients with esophageal squamous cell carcinoma (ESCC) and to explore the biological effects of HMGCS1 on the metastatic ability of ESCL cells. Methods: Tissue samples from 6 patients who underwent ESCC surgeries in our hospital were collected and divided into non-metastatic and lung metastatic groups. Protein spectrum sequencing analysis together with GEPIA database was performed to screen differentially expressed proteins. Western blot and qPCR were used to determine HMGCS1expression in esophageal epithelial cells and ESCC cells. Immunohistochemical staining was performed to determine HMGCS1expression in tissue sections from 121 patients with ESCC. Cox proportional survival risk model was enrolled to analyze the survival risk factors of ESCC patients, and multivariate correlation analysis was used for the analysis of the association of HMGCS1 with the clinicopathology of ESCC patients. Furthermore, Kaplan-Meier analysis was employed to analyze the effect of HMGCS1 on the prognosis of ESCC patients. The migration and invasion ability of ESCC cells were detected by scratch and Transwell. Results: We identified 45 significantly up-regulated and 51 down-regulated (including HMGCS1) proteins in the tumor tissues of patients with lung metastasis, compared with those without metastasis. GEPIA verified that HMGCS1 was down-regulated in esophageal cancer. Western blot and qPCR results further validated that HMGCS1 expression in ESCC cells was significantly lower than that in normal esophageal epithelium. Immunohistochemical staining of 121 patients with ESCC confirmed that the expression of HMGCS1 in ESCC was significantly lower than that in normal esophageal tissues. Additionally, the expression of HMGCS1 in patients with lymph node metastasis was significantly lower than that in patients without lymph node metastasis (P < 0.05). Cox survival risk analysis showed that T stage[HR: 2.118 (1.020～4.399)], lymph node metastasis[HR: 2.127 (1.466～5.584)]and low HMGCS1 expression were risk factors[HR: 0.413 (0.211～0.807)]for survival of ESCC. Multivariate correlation analysis indicated that HMGCS1 expression was significantly correlated with lymph node metastasis. Kaplan-Meier survival analysis demonstrated that patients with low HMGCS1expression had a poor prognosis. Furthermore, we found that overexpression of HMGCS1 markedly inhibited the migration and invasion ability of ESCC cells (P < 0.05). Conclusion: HMGCS1 could suppress the metastasis of ESCC cells and its expression was positively correlated with the prognosis of ESCC patients. [ABSTRACT FROM AUTHOR]