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OBJECTIVES: To establish a simple, valid, and acceptable method of predicting peak oxygen uptake (VO2peak) in patients with chronic fatigue syndrome (CFS), which could provide a basis for subsequent exercise prescription at an appropriate intensity as part of a clinical rehabilitation programme. METHODS: A total of 130 patients who met UK research criteria for CFS were taken from consecutive referrals for chronic fatigue to the University Department of Medicine at Withington Hospital, Manchester. VO2peak was determined using an incremental graded exercise test to exhaustion. Respiratory gas exchange, work rate, and heart rate were monitored throughout. RESULTS: In all patients, VO2peak was found to correlate strongly and significantly with peak work rate (WRpeak) during testing (r2 = 0.88, p<0.001). In patients who exercised for longer than two minutes (n = 119), regression analysis established the relation as Vo2peak = 13.1 x WRPpeak + 284, where VO2 is given in ml/min and WR in W. The mean error between the measured VO2peak and the predicted value was 10.7%. The relation between increase in work rate and oxygen uptake across the group was highly significant (r2 = 0.87, p<0.001), and given as VO2increase = 12.0 x WRincrease, this value being similar to that expected for healthy individuals. Almost all (97%) subjects reported no exacerbation of symptoms after maximal exercise testing. CONCLUSIONS: Using a simple to administer maximal exercise test on a cycle ergometer, it is possible to predict accurately the VO2peak of a patient with CFS from peak work rate alone. This value can then be used as an aid to setting appropriate exercise intensity for a rehabilitation programme. The increase in VO2 per unit increase in workload was consistent with that expected in healthy individuals, suggesting that the physiological response of the patients measured here was not abnormal. Contrary to the belief of many patients, maximal exercise testing to the point of subjective exhaustion proved to be harmless, with no subjects suffering any lasting deterioration in their condition after assessment.