The impact of cerebral Epo in the regulation of the hypercapnic ventilatory response (HcVR) is controversial. While we reported that cerebral Epo does not affect the central chemosensitivity in C57Bl6 mice receiving an intracisternal injection of sEpoR (the endogenous antagonist of Epo), a recent study in transgenic mice with constitutive high levels of human Epo in brain and circulation (Tg6) and in brain only (Tg21), showed that Epo blunts the HcVR, maybe by interacting with central and peripheral chemoreceptors. High Epo serum levels in Tg6 mice lead to excessive erythrocytosis (hematocrit about 80-90%), the main symptom of chronic mountain sickness (CMS). These latter results support the hypothesis that reduced central chemosensitivity accounts for the hypoventilation observed in CMS patients. To solve this intriguing divergence, we re-evaluate HcVR in Tg6 and Tg21 mouse lines, by assessing the metabolic rate (O2 consumption; and CO2 production), a key factor modulating ventilation, which effect was not considered in the previous study. Our results showed that the decreased HcVR observed in Tg6 mice (~70% reduction; p<0.01) was due to a significant decrease in the metabolism (~40%; p<0.0001) rather than Epo's effect on CO2 chemosensitivity. Additional analysis in Tg21 mice did not revealed differences of HcVR or metabolism. We concluded that cerebral Epo does not modulate the central chemosensitivity system, and that a metabolic effect upon CO2 inhalation is responsible for decreased HcVR observed in Tg6 animals. As CMS patients also show decreased HcVR, our findings might help to better understand respiratory disorders at high altitude.