Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder with no known underlying mechanisms, diagnostic tools, or treatments. Multiple areas of dysfunction have been extensively studied, but rarely examined together. We recruited age- and sex-matched ME/CFS patients and healthy controls for a multi-modal study examining energy metabolism, immune profiles and plasma protein levels. Adenosine monophosphate (AMP) were higher in immune cells from MECFS patients, with a similar but non-signficant trend observed in plasma. Additionally, immune cells showed higher levels of adenosine diphosphate (ADP) and a reduced adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio. These findings imply decreased ATP generation and the presence of energy stress within the immune cell population. Adaptive immune cell populations were skewed towards less mature effector subsets of CD4+, CD8+ and γδ T cells, and proportions of CD1c+CD141- conventional DC type 2 (cDC2) and CD56lowCD16+ terminal natural killer (NK) cells were also reduced. Elevated levels of plasma proteins associated with thrombus formation and vascular reactivity may contribute to the endothelial dysfunction observed in ME/CFS patients. Using Classification and Regression Tree (CART) modelling, we identified variables from each mode of investigation with strong predictive potential for ME/CFS. Together, this study provides new insights intothe somatic symptoms and underlying biology of ME/CFS.