This study was performed to test the hypothesis that administration of recombinant human erythropoietin (rHuEpo) in humans increases VO₂max by augmenting maximal oxygen carrying capacity of the blood. Systemic and leg oxygen delivery and oxygen uptake were studied during exercise in eight subjects prior to and following 13 weeks of rHuEpo treatment, and after isovolemic hemodilution to the same hemoglobin concentration observed before the start of rHuEpo administration. At peak exercise, leg oxygen delivery was increased from 1777.0 ± 102.0 before rHuEpo treatment to 2079.8 ± 120.7 ml.min^-1 after treatment. Following hemodilution oxygen delivery was decreased to the pre value (1710.3 ± 138.1 ml.min^-1). Fractional leg arterial O₂ extraction was unaffected at maximal exercise, and hence maximal leg oxygen uptake increased from 1511.0 ± 130.1 ml.min^-1 before treatment to 1793.0 ± 148.7 ml.min^-1 with rHuEpo, and decreased after hemodilution to 1428.0 ± 111.6 ml.min^-1. Pulmonary O₂ uptake at peak exercise increased from 3950.0 ± 160.7 before administration to 4254.5 ± 178.4 ml.min^-1 with rHuEpo, and decreased to 4059.0 ± 161.1 ml.min^-1 with hemodilution (P=0.22 compared to pre rHuEpo). Blood buffer capacity remained unaffected by rHuEpo treatment and hemodilution. The augmented hematocrit did not compromise peak cardiac output. In summary, in healthy humans rHuEpo increases VO₂max due to augmented systemic and muscular peak O₂ delivery.