To study the capacity for moderate endurance exercise and change in metabolic fuel utilization during adaptation to a ketogenic diet, six moderately obese, untrained subjects were fed a eucaloric, balanced diet (base line) for 2 wk, followed by 6 wk of a protein-supplemented fast (PSF), which provided 1.2 g of protein/kg ideal body wt, supplemented with minerals and vitamins. The mean weight loss was 10.6 kg. The duration of treadmill exercise to subjective exhaustion was 80% of base line after 1 wk of the PSF, but increased to 155% after 6 wk. Despite adjusting up to base line, with a backpack, the subjects' exercise weight after 6 wk of dieting, the final exercise test was performed at a mean of 60% of maximum aerobic capacity, whereas the base-line level was 76%. Resting vastus lateralis glycogen content fell to 57% of base line after 1 wk of the PSF, but rose to 69% after 6 wk, at which time no decrement in muscle glycogen was measured after >4 h of uphill walking. The respiratory quotient (RQ) during steady-state exercise was 0.76 during base line, and fell progressively to 0.66 after 6 wk of the PSF. Blood glucose was well maintained during exercise in ketosis. The sum of acetoacetate and beta hydroxybutyrate rose from 3.28 to 5.03 mM during exercise after 6 wk of the PSF, explaining in part the low exercise RQ. The low RQ and the fact that blood glucose and muscle glycogen were maintained during exhausting exercise after 6 wk of a PSF suggest that prolonged ketosis results in an adaptation, after which lipid becomes the major metabolic fuel, and net carbohydrate utilization is markedly reduced during moderate but ultimately exhausting exercise.