Ten anemic hemodialysis patients were treated for 6-14 months with human recombinant erythropoietin (EPO). The mean hemoglobin level significantly increased by 42%. Pretreatment skeletal muscle heat production rate at rest, as determined by direct microcalorimetry, was lower than normal (p < 0.03), indicating decreased metabolic activity. ATP levels in muscle were inversely correlated (rs = -0.66, p < 0.05) with the heat production values. The latter significantly increased by about 40% and were almost normalized by the therapy, whereas a decline in the mean ATP level was seen, from 14.8 to 13.2 μmol g-1 of muscle (p = 0.06). We hypothesize that the lowered ATP concentration in muscle after treatment might have been due to an enhanced ATP consumption in parallel with improved muscle strength. Alternatively, since acidosis prior to treatment might have altered the equilibrium state of the creatine kinase reaction towards ATP production, it is possible that the improved oxygenation after EPO had increased pH in the muscle and catalyzed the transfer of phosphate from ATP to PCr. It is concluded that EPO treatment can almost normalize the decreased muscle metabolic rate in hemodialysis patients, and that the anemia per se seems to be an important cause of the deranged metabolism in striated muscle