Apart form elevating erythropoiesis, erythropoietin (Epo) exerts protective functions in brain, retina and heart upon ischemic injury. However, physiological non-erythroid functions of Epo remain unclear. Here we use a transgenic mouse line (Tg21) constitutively overexpressing human Epo in brain to investigate Epo's impact on ventilation upon hypoxic exposure. Tg21 mice showed improved ventilatory response to severe acute hypoxia and moreover improved ventilatory acclimatization to chronic hypoxic exposure. Furthermore, following bilateral transection of carotid sinus nerves that uncouples the brain from the carotid body, Tg21 mice adapted their ventilation to acute severe hypoxia while chemodenervated wild type (wt) animals developed a life-threatening apnea. These results imply that Epo in brain modulates ventilation. Additional analysis revealed that Epo receptor is expressed in the main brainstem respiratory centers and suggested that Epo stimulates breathing control by alteration of catecholaminergic metabolism in brainstem. Interestingly, we observed that the HVR (hypoxic ventilatory response) was enhanced in female Tg21 mice. In summary, our results suggest that Epo controls ventilation at central (brainstem) and peripheral (carotid body) levels in a gender-dependent manner.