Objective:To explore the metabolic regulations of different Traditional Chinese Medicine (TCM) syndromes in the diabetic patients with high risk for foot ulceration.Methods:Based on gas chromatography-mass spectrometer and multi-dimensional data processing methods, the metabolomics analysis was used to compare the serum metabolites profile of healthy people (32 cases) and the high-risk foot patients in Cold and Blood Stagnation syndrome (44 cases), Heat-toxin hurting Yin syndrome (54 cases), and Qi-Blood deficiency syndrome (33 cases), who were hospitalized at Shanghai TCM-Integrated Hospital from Apirl to December, 2018.Results:This study suggested that compared with healthy people, the diabetic patients with high risk for foot ulceration showed significantly lower serum level of urea [(2.41 ± 1.57)×10 5vs. (3.32 ± 2.10)×10 5], L-leucine [(4.94 ± 3.15)×10 5vs. (6.39 ± 3.57)×10 5], aspartic acid [(3.94 ± 4.48)×10 5vs. (9.62 ± 6.93)×10 5], 9H-purine [(1.74 ± 1.95)×10 5vs. (3.34 ± 2.23)×10 5] ( P<0.05 or P<0.01), while higher level of d-Glucose [(3.72 ± 1.71)×10 5vs. (2.21 ± 1.32)×10 5] and d-glucopyranose [(3.32 ± 2.10)×10 5vs. (1.35 ± 1.43)×10 5] ( P<0.01). Energy metabolism, amino acid metabolism and sugar metabolism were mainly involved. the content of L-tyrosine in the group of patients with Cold and Blood Stagnation syndromewas significantly higher than that in healthy people. The urea, purine, leucine, aspartic acidcontent in patients of Heat-toxin hurting Yin syndrome were significantly lower than that in healthy people. The purine content in patients of Qi and Blood Deficiency Syndrome was significantly lower than that in healthy people. Compared with the syndrome of Heat-toxin hurting Yin syndrome, patients in Cold and Blood Stagnation syndrome showed a significantly higher content of beta-1-galactopyranoside and butanoic acid. Compared to the Qi-Blood deficiency syndrome, serum urea level in patients of Heat-toxin hurting Yin syndrome was significantly higher than those in the patients of other two TCM syndromes. Conclusions:The serum metabolomics profiling differentiate three TCM-syndrome in high-risk DF patients, which can provide objective basis for clinical TCM syndrome differentiation and treatment of high-risk diabetic foot patients.