The brain is highly sensitive to environmental hypoxia. Little is known, however, about the neuropsychological effects of high altitude residence in the developing brain. We recently described only minor changes in processing speed in native Bolivian children and adolescents living at approximately 3700 m. However, evidence for loss of cerebral autoregulation above this altitude (4000 m) suggests a potential threshold of hypoxia severity over which neuropsychological functioning may be compromised. We conducted physiological and neuropsychological assessments in 62 Bolivian children and adolescents living at La Paz (-3700 m) and El Alto (-4100 m) in order to address this issue. Groups were equivalent in terms of age, gender, social class, schooling, parental education and genetic admixture. Apart from percentage of hemoglobin saturated with oxygen in arterial blood (%SpO[subscript 2]), participants did not differ in their basal cardiac and cerebrovascular performance as explored by heart rate, mean arterial pressure, end-tidal carbon dioxide, and cerebral blood flow velocity at the basilar, anterior, middle and posterior cerebral arteries. A comprehensive neuropsychological assessment was administered, including tests of executive functions, attention, memory and psychomotor performance. Participants living at extreme altitude showed lower levels of performance in all executive tests (Cohen effect size = -0.91), whereas all other domains remained unaffected by altitude of residence. These results are compatible with earlier physiological evidence of a transitional zone for cerebral autoregulation at an altitude of 4000 m. We now show that above this threshold, the developing brain is apparently increasingly vulnerable to neuropsychological deficit.