Background: Myalgic encephalomyelitis chronic fatigue syndrome (ME/CFS) ă is a common debilitating disorder associated with an intense fatigue, a ă reduced physical activity, and an impaired quality of life. There are no ă established biological markerof the syndrome. The etiology is unknown ă and its pathogenesis appears to be multifactorial. Various stressors, ă including intense physical activity, severe infection, and emotional ă stress are reported in the medical history of ME/CFS patients which ă raises the question whether any physiological and biological ă abnormalities usually found in these patients could be indicative of the ă etiology and/or the quality-of-life impairment. ă Methods: Thirty-six patients and 11 age-matched healthy controls were ă recruited. The following variables that appear to address common ă symptoms of ME/CFS were studied here: (1) muscle fatigue during exercise ă has been investigated by monitoring the compound muscle action potential ă (M-wave); (2) the excessive oxidative stress response to exercise was ă measured via two plasma markers (thiobarbituric acid reactive ă substances: TBARS; reduced ascorbic-acid: RAA); (3) a potential ă inflammatory component was addressed via expression of CD26 on ă peripheral blood mononuclear cells; (4) quality-of-life impairment was ă assessed using the London Handicap Scale (LHS) and the Medical Outcome ă Study Short Form-36 (SF-36). The medical history of each patient, ă including the presence of stressors such as intense sports practice, ă severe acute infection and/or severe emotional stress was documented. ă Results: We observed that: (1) there were striking differences between ă cases and controls with regard to three biological variables: ă post-exercise M-wave, TBARS variations and CD26-expression at rest; (2) ă each of these three variables correlated with the other two; (3) ă abnormalities in the biomarkers associated with health-related quality ă of life: the LHS score was negatively correlated with the ă exercise-induced TBARS increase and positively correlated with ă CD26-expression while the pain component of SF-36 was negatively ă correlated with CD26-expression; (4) the TBARS increase and the M-wave ă decrease were the highest, and the CD26-expression level the lowest in ă patients who had been submitted to infectious stressors. ă Conclusion: In ME/CFS patients, severe alterations of the muscle ă excitability, the redox status, as well as the CD26-expression level are ă correlated with a marked impairment of the quality-of-life. They are ă particularly significant when infectious stressors are reported in the ă medical history.