Objective To screen the prognosis ⁃ related gene SLC5A12 of esophageal squamous cell carcinoma by protein profiling and explore its effect on the malignant phenotype of ESCC cells. Methods Protein profiling was performed to screen for differentially expressed proteins in ESCC，and public databases were used to screen for SLC5A12，a gene associated with prognosis in ESCC，and to analyze the relationship between SLC5A12 expression and prognosis in ESCC patients in the database. Immunohistochemical staining of tissue microarrays made from paired tumor and normal tissues of 117 ESCC patients with perfect follow⁃up information in the biospeci⁃ men database was performed to analyze the expression of SLC5A12 in ESCC and its relationship with the clinicopa⁃ thology and prognosis of patients. Small interfering RNA knocked down the expression of SLC5A12 in ESCC cells， and the proliferation，invasion and migration ability of the cells were detected. Results A total of 235 protein expressions were upregulated and 362 protein expressions were downregulated in ESCC，in which SLC5A12 expres⁃ sion was significantly higher than that in normal tissues（log2 fold = 1.33，P = 0.0004）. SLC5A12 expression in ESCC patients in TCGA was significantly higher than that in normal tissues and esophageal adenocarcinoma，and N stage and SLC5A12 expression were risk factors for patient survival factors，and SLC5A12 expression was signifi⁃ cantly associated with overall survival［HR = 2.74，95%CI：1.27 ~ 5.94，P = 0.012］and disease⁃specific survival ［HR = 3.14，95%CI：1.24 ~ 7.95，P = 0.02］in ESCC patients. Immunohistochemical staining of tissue microarraysconfirmed that SLC5A12 expression was significantly higher in ESCC than in normal tissues and significantly higher in patients with lymph node metastases than in those without metastases. SLC5A12 expression levels were signifi⁃ cantly correlated with overall survival（P < 0.000 1），pathological stage（P < 0.001）and lymph node metastases （P < 0.001）in ESCC patients. The proliferation，invasion and migration ability of ESCC cells were significantly reduced after knockdown of SLC5A12 expression. Conclusions SLC5A12 expression in ESCC was significantly higher than that in normal tissues and significantly correlated with the prognosis，pathological stage and lymph node metastasis of patients，and SLC5A12 could promote the malignant phenotype progression of ESCC cells.