We used transgenic mice constitutively over-expressing erythropoietin ("tg6" mice) and wild-type (wt) mice to investigate whether the high hematocrit (hct), consequence of Epo over-expression affected: (1) the normoxic ventilation (over(V, ̇)E) and the acute hypoxic ventilatory response (HVR) and decline (HVD), (2) the increase in ventilation observed after chronic exposure to hypobaric hypoxia (430 mmHg for 21 days), (3) the respiratory "blunting", and (4) the erythrocythemic response induced by chronic hypoxia exposure. over(V, ̇)E was found to be similar in tg6 and wt mice in normoxia (F IO2 = 0.21). Post-acclimation over(V, ̇)E was significantly elevated in every time point in wt mice at F IO2 = 0.10 when compared to pre-acclimation values. In contrast, tg6 mice exhibited a non-significant increase in over(V, ̇)E throughout acute hypoxia exposure. Changes in over(V, ̇)E are associated with adjustments in tidal volume (VT). HVR and HVD were independent of EE in tg6 and wt mice before chornic hypoxia exposure. HVR was significantly greater in wt than in tg6 mice after chronic hypoxia. After acclimation, HVD decreased in tg6 mice. Chronic hypoxia exposure caused hct to increase significantly in wt mice, while only a marginal increase occurred in the tg6 group. Although pre-existent EE does not appear to have an effect on HVR, the observation of alterations on VT suggests that it may contribute to time-dependent changes in ventilation and in the acute HVR during exposure to chronic hypoxia. In addition, our results suggest that EE may lead to an early "blunting" of the ventilatory response. © 2007 Elsevier B.V. All rights reserved.