This work attempts to evaluate the cognitive aspects of the acclimatization ability of mice submitted to simulated altitude. Critical altitudes were detected by evaluating open field activity, combined or not with object recognition tasks, at different acute simulated altitudes. Results showed impaired cognitive abilities at ≈3,733 m and above. To evaluate acclimatization capabilities, mice submitted to hypobaric hypoxia at ≈5,000 m for 1 wk were tested for learning and memory performances with classical eyeblink conditioning at the same altitude or at land altitude. Results showed total acclimatization in mice conditioned at ≈5,000 m but no improved performance in those conditioned at land altitudes compared with controls. Selected brain sites of conditioned animals were analyzed by immunohistochemistry to detect expression of the protein product of the protooncogene c-fos (Fos) in relation to both motor learning processes and hypobaric conditions. In the nucleus of the solitary tract, a higher expression of Fos was found in the acute hypobaric conditioned animals than in control conditioned and nonconditioned animals. Similar patterns between groups were found in the other brain areas, mainly in the piriform cortex and area 1 of the cingulate cortex and in the hippocampus. Differences between hemispheres were detected only in acute hypobaric animals. The present results show that acclimatization to high altitude prevents the impairment of classical eyeblink conditioning evoked by hypobaric hypoxic conditions but does not improve this task when acquired under land conditions, although it could diminish the activation requirements for its performance. Copyright © 2007 the American Physiological Society.