Background: ME/CFS is a complex disease with unclear etiology. Current diagnostic criteria lack objective laboratory measures. Aims: This study aimed to investigate the plasma proteomic profile of ME/CFS patients and determine any differentially expressed proteins compared to controls. Methods: Plasma samples obtained from 19 ME/CFS patients and 9 controls underwent analysis (Somalogic, Inc, CO). The ME/CFS patients met the National Academy of Medicine criteria for the disease. Samples were collected from a mixed venous compartment. Statistical analysis and a Mixed Graphical Model were used to identify candidate biomarker. Results: Among ~7000 proteins detected, ~400 were differentially expressed between patients and controls (False Discovery Rate<0.05 and Absolute Fold Change ?1.5). Selectin E (SELE), ATP Synthase Subunit F6 (ATP5PF), and Transcobalamin 2 (TCN2) were identified as top candidates. A classifier of these proteins in pulmonary artery blood of patients were distinguishable from controls (AUC =0.99). Conclusion: The study highlighted potential biomarkers for ME/CFS, the top candidates of which are involved in inflammation, cellular energy metabolism, and Vitamin B12 transport. The plasma proteomic signature identifies ME/CFS from normals and suggests that the disease?s pathophysiology is driven by abnormalities of aerobic metabolism, vascular dysregulation, and Vitamin B12 metabolism.