Hypoxia damages multiple organ systems especially those with high oxygen utilization such as the central nervous system. The purpose of this study was to compare the neuropathological and neuropsychological effects of hypoxia in patients with either carbon monoxide poisoning or obstructive sleep apnea. Neuroimaging revealed evidence of hippocampal atrophy in both groups although a linear relationship between hippocampal volume and memory performance was found only for selected tests and only in the sleep apnea group. There were significant correlations between hippocampal volume and performance on measures related to nonverbal/information processing. Generalized brain atrophy, as measured by the ventricle-to-brain ratio, was more common in the carbon monoxide poisoning group compared to the obstructive sleep apnea group. Performance on tests of executive function improved following treatment with nasal continuous positive airway pressure treatment in the obstructive sleep apnea group but there was no associated improvement in general intellectual function. We found that hypoxia due to obstructive sleep apnea and CO poisoning resulted in neuropathological changes and neuropsychological impairments. The observed group differences provide insight into the relationship between etiology of injury, neuropathological changes, and clinical presentation.