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Objective: To analyze the differential small molecule metabolites of plasma between esophageal cancer patients and healthy controls using liquid chromatography-mass spectrometry (LC-MS) as potential biomarkers for early diagnosis of esophageal cancer.Methods: 53 plasma samples from esophageal cancer patients matched with 53 plasma samples from healthy controls were collected for metabolites analysis with LC-MS.The data obtained were analyzed using MPP (Agilent), followed by the HMDB database to identify the differentially expressed compounds.Results: 41 compounds showed significant difference between esophageal cancer patients and healthy controls (P <0.05, fold change ≥ 2), in which 36 molecules were up-regulated and 5 molecules were down-regulated in esophageal cancer.After matched with the data from HMDB database, 19 molecules were identified as follows:phosphatidylserine;L-Acetyl carnitine;12-oxo-20-dihydroxy-leukotriene B4;5-β-cyprinol sulfate;L-Urobilinogen;Lithocholic acid taurine conjugate;phosphatidicacid;desmosine;isodesmosine;phosphatidyl choline;9-carboxy-gama-tocotrienol;Lithocholate 3-O-glucuronide;osphatidylinositol;PE;LysoPC(22:2(13Z, 16Z));Ganglioside GM2(d18: 1/24: 1(15Z));CL(20:4(8Z,11Z, 14Z, 17Z)/20: 1(11Z)/18:2(9Z,12Z)/18:2(9Z,12Z)) and Sphinganine 1-phosphate.These compounds still need to be identified by tandem mass spectrometry and related technologies.Conclusion: Plasma metabolites spectrum based on LC-MS analysis provides significant discrimination of esophageal cancer from healthy subjects, which suggests a potential application value in screening and early diagnosis of esophageal cancer.