Individuals with chronic fatigue syndrome (CFS) experience a number of somatic complaints including severe, disabling fatigue, and exercise intolerance. We hypothesized that hypovolemia, through its interaction with central hemodynamics, would contribute to the exercise intolerance associated with this disorder. We examined blood volume, peak aerobic power, habitual physical activity, fatigue level, and their interrelations to understand the physiological basis of this disorder. Seventeen patients who met the Centers for Disease Control criteria for CFS and 17 age-matched controls participated in the study. Blood volume was assessed using a single bolus injection of Evans blue dye. Peak oxygen consumption was measured during exercise on an upright cycle ergometer. Supine cardiac output and stroke volumes were measured using CO₂ rebreathing. Questionnaires were used to assess habitual physical activity and fatigue. Patients displayed a trend for a 9% lower blood volume (58.3 ± 2.1 vs. 64.2 ± 2.5 ml/kg, P = 0.084) and had a 35% lower peak oxygen consumption (22.0 ± 1.2 vs. 33.6 ± 1.9 ml/kg, P < 0.001). These two variables were highly related within the patients (r = 0.835, P < 0.001) and the controls (r = 0.850, P < 0.001). Peak ventilation and habitual physical activity were significantly lower in the patients. Fatigue level was not related to any of the measured physiological parameters within the CFS group. In conclusion, individuals with CFS have a significantly lower peak oxygen consumption and an insignificant trend toward lower blood volume compared with controls. These variables were highly related in both subject groups, indicating that blood volume is a strong physiological correlate of peak oxygen consumption in patients with CFS.