Acclimatization to hypoxia relies on elevated ventilation and erythropoietic activity. We recently showed that erythropoietin (Epo) links both responses: apart from erythropoiesis, cerebral and plasma Epo interferes with the central (brainstem) and peripheral (carotid body) respiratory centers. Knowing that women cope better than men to reduced oxygen supply we analyzed the hypoxic ventilatory response in transgenic female mice with elevated Epo levels in brain only (Tg21), or in brain and plasma (Tg6) or in wild type animals injected with recombinant human Epo. Exposure to moderate and severe hypoxia revealed that the presence of transgenic or recombinant human Epo extensively increases the hypoxic ventilatory response in female mice compared to their male siblings. Finally, human volunteers were injected with recombinant human Epo and subsequently exposed to 10% oxygen. Compared to men, the hypoxic ventilatory response was significantly increased in women. We conclude that Epo exerts a gender-dependent impact on hypoxic ventilation that involves sexual hormones. In another line of investigation, we show that the optimal hematocrit for maximal performance is 0.57 to 0.65. On the other hand it is known that high doses of injected Epo crosses the blood brain barrier causing neurologic effects. We present a new role by which Epo augments exercise performance without altering the hematological parameters. Tg21 or wild-type mice (WT) treated with a high dose of rhEpo (WT+rhEpo) demonstrate a dramatic improvement in maximal exercise performance independent of changes in blood and cardiovascular parameters. This novel finding builds a more complete understanding regarding the central effects of endogenously produced and exogenously applied Epo on exercise performance.