Erythropoietin (Epo) administration improves aerobic exercise capacity and insulin sensitivity in renal patients, and also increases resting energy expenditure (REE). Similar effects are observed in response to endurance training. The aim was to compare the effects of endurance training with erythropoiesis-stimulating agent (ESA) treatment in healthy humans. Thirty-six healthy untrained men were randomized to 10 weeks of either: 1) placebo (n=9), 2) ESA (n=9), 3) endurance training (n=10), or 4) ESA and endurance training (n=8). In a single blinded design, ESA/placebo was injected once weekly. Training consisted of biking for 1h at 65% of wattmax 3 times/week. Measurements performed before and after the intervention: body composition, maximal oxygen uptake, insulin sensitivity, REE, and palmitate turnover. Uncoupling protein 2 (UCP2) mRNA levels were assessed in skeletal muscle. Fat mass decreased after training (p=0.003), whereas ESA induced a small but significant increase in intrahepatic fat (p=0.025). Serum free fatty-acid (FFA) levels and palmitate turnover decreased significantly in response to training, whereas the opposite pattern was found after ESA. REE corrected for lean body mass increased in response to ESA and training and muscle UCP2 mRNA levels increased after ESA (p=0.035). Insulin sensitivity increased only after training (p=0.011). Conclusions: 1) Insulin sensitivity is not improved after ESA treatment despite improved exercise capacity, 2) The calorigenic effects of ESA may be related to increased UCP2 gene expression in skeletal muscle, 3) Training and ESA exert opposite effects on lipolysis under basal conditions, increased FFA levels and liver fat fraction was observed after ESA treatment.