It is documented that chronic fatigue syndrome (CFS) combines enhanced oxidative stress with altered muscle excitability. We hypothesized that these disorders may be accentuated when severe infection preceded the CFS symptoms. This case-control study compared 55 CFS patients to a matched control group of 40 healthy subjects. In twenty-five CFS patients, severe infection was reported within the three to seven month period preceding the CFS symptoms. The others had practiced sport at high level. Plasma concentrations of potassium, a marker of lipid peroxidation (thiobarbituric acid reactive substances, TBARS), and an endogenous antioxidant (reduced ascorbic acid, RAA) were measured. Action potential (M-wave) was evoked in the vastus lateralis muscle to explore the muscle membrane excitability. All subjects performed a maximal incremental cycling exercise. Compared to control subjects, all CFS patients presented an elevated resting TBARS level and, during and after exercise, an altered M-wave configuration. History of infection was associated with marked significant increase in resting TBARS level, enhanced M-wave alterations, and also reduced exercise-induced potassium efflux. The magnitude of exercise-induced M-wave alterations was proportional to the baseline TBARS level. Severe infection preceding CFS seems to constitute a stressor inducing altered blood oxidant status and a reduced muscle excitability at work.