Background: Thymoma-associated myasthenia gravis (TAMG) is a well-described subtype of Myasthenia gravis (MG). Nevertheless, the detailed proteins and bioprocess differentiating TAMG from TAMG (-) thymoma have remained unclear. Methods: The proteomics and metabolomics were carried out on serum samples from thymoma group (n = 60, TNMG), TAMG (+) thymoma group (n = 70, TAMG (+)), and TAMG (-) thymomas group (n = 62, TAMG (-)), and controls (n = 159). groups. Proteomics and metabolomics analyses, including weighted gene co-expression network analysis (WGCNA), was conducted to detect the hub proteins and metabolomics processes that could differentiate TAMG (+) from TAMG (-) thymomas. MetaboAnalyst was used to examine the integration of proteomic and metabolomic analysis to differentiate TAMG (+) from TAMG (-) thymomas. Results: The of module-trait correlation of WGCNA analysis identified KRT1, GSN, COL6A1, KRT10, FOLR2, KRT9, KRT2, TPI1, ARF3, LYZ, ADIPOQ, SEMA4B, IGKV1-27, MASP2, IGF2R was associated with TAMG (+) thymomas. In addition, organismal systems-immune system and metabolism-biosynthesis of other secondary metabolites were closely related to the mechanism of TAMG (+) pathogenesis. Conclusion: Our integrated proteomics and metabolomics analysis supply a systems-level view of proteome changes in TAMG (+), TAMG (-) thymomas and exposes disease-associated protein network alterations involved in.