Objective：The current study aims to explore the potential metabolic differences caused by systemic lupus erythematosus (SLE)and rheumatoid arthritis(RA)，the characteristics of serum metabolic profiles of patients with SLE and RA were analyzed. Methods：Serum samples were respectively collected from SLE patients，RA patients，and healthy volunteers. Hydrophilic interaction and ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry(HILIC UHPLC-Q-TOF MS)was performed to analyze the full spectrum of these serum samples. The significantly altered metabolites were enriched by orthogonal partial least squares - discriminant analysis(OPLS -DA)models combined with univariate statistical analysis. The receiver operating characteristic(ROC)curve was used to evaluate the diagnostic efficacy of the candidate serum metabolite biomarkers. KEGG pathway enrichment analysis was conducted to uncover the significantly altered pathways in each disease group. Results：The serum profiles showed remarkable differences among the SLE group，RA group，and the control group. Five significantly altered metabolites， including 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphoethanolamine，taurine，hexadecanedioic acid，(+-)12-hydroxyeicosantetraenoic acid(12 - HETE)and hypoxanthine，were proposed as potential diagnostic biomarkers. Furthermore，7 KEGG pathways，such as retrograde endocannabinoid signaling pathway，significantly altered in the SLE group when compared with the control group or RA group. Conclusion：Untargeted metabolomics study could be used to reveal the discrepancy of serum metabolic profiles among SLE patients，RA patients，and healthy people. The screened metabolite biomarkers and significantly altered pathways are expected to provide novel insights into the diagnosis and treatment of aforementioned diseases.