The aim of the current study was to investigate the levels of interleukin‐6 (IL‐6), its soluble receptors (sIL‐6R and sgp130) and F₂‐isoprostanes, at rest and during exercise, in patients with chronic fatigue syndrome (CFS). Six male CFS patients and six healthy controls performed an incremental exercise test to exhaustion and a submaximal exercise bout to exhaustion. Blood samples taken in the submaximal test at rest, immediately post‐exercise and 24 h post‐exercise were analyzed for IL‐6, sIL‐6R, sgp130 and F₂‐isoprostanes. A further 33 CFS and 33 healthy control participants gave a resting blood sample for IL‐6 and sIL‐6R measurement. During the incremental exercise test only power output at the lactate threshold was lower (P<0.05) in the CFS group. F₂‐isoprostanes were higher (P<0.05) in CFS patients at rest and this difference persisted immediately and 24 h post‐exercise. The exercise study found no differences in IL‐6, sIL‐6R or sgp130 at any time point between groups. In the larger resting group, there were no differences in IL‐6 and sIL‐6R between CFS and control groups. This investigation has demonstrated that patients with CFS do not have altered plasma levels of IL‐6, sIL‐6R or sgp130 either at rest or following exercise. F₂‐isoprostanes, however, were consistently higher in CFS patients.