This study examined the effects of maximal incremental exercise on cerebral oxygenation in chronic fatigue syndrome (CFS) subjects. Furthermore, we tested the hypothesis that CFS subjects have a reduced oxygen delivery to the brain during exercise. Six female CFS and eight control (CON) subjects (similar in height, weight, body mass index and physical activity level) performed an incremental cycle ergometer test to exhaustion, while changes in cerebral oxy-haemoglobin (HbO2), deoxy-haemoglobin (HHb), total blood volume (tHb = HbO2 + HHb) and O2 saturation [tissue oxygenation index (TOI), %)] was monitored in the left prefrontal lobe using a near-infrared spectrophotometer. Heart rate (HR) and rating of perceived exertion (RPE) were recorded at each workload throughout the test. Predicted VO2peak in CFS (1331 ± 377 ml) subjects was significantly (P ≤ 0·05) lower than the CON group (1990 ± 332 ml), and CFS subjects achieved volitional exhaustion significantly faster (CFS: 351 ± 224 s; CON: 715 ± 176 s) at a lower power output (CFS: 100 ± 39 W; CON: 163 ± 34 W). CFS subjects also exhibited a significantly lower maximum HR (CFS: 154 ± 13 bpm; CON: 186 ± 11 bpm) and consistently reported a higher RPE at the same absolute workload when compared with CON subjects. Prefrontal cortex HbO2, HHb and tHb were significantly lower at maximal exercise in CFS versus CON, as was TOI during exercise and recovery. The CFS subjects exhibited significant exercise intolerance and reduced prefrontal oxygenation and tHb response when compared with CON subjects. These data suggest that the altered cerebral oxygenation and blood volume may contribute to the reduced exercise load in CFS, and supports the contention that CFS, in part, is mediated centrally.