Although high altitude exposure results in persistent impairment in neurocognitive function, it is unclear the extent to which grey and white matter, and vasomotor function are altered. The purpose of this study was to assess regional cerebrovascular reactivity (CVR), and the volumetric changes in grey and white matter one week following an expedition to 5,050m. The expedition involved a week in Kathmandu (1,400m), an 8-day trek from Lukla (2,860m) to the Pyramid Laboratory at 5,050m where subjects remained for 3 weeks prior to descending to Kathmandu over a 4-day period. Healthy humans (n=6, 1 female, age= 31.8 ± 3.7 years; BMI = 27.0 ± 3.6 kg/m2; mean ± SE) underwent baseline and follow-up structural (T1-weighted imaging) and functional (blood oxygen level dependent, BOLD) MR imaging (3T) at rest and during a CO2 CVR test. An end-tidal forcing system was used to control end-tidal gases during two steps of hypocapnia (PETCO2 reduced by 10 and 5 mmHg from baseline for 2 min by active hyperventilation) and three steps of hypercapnia (PETCO2 increased by 5, 10, and 15 mmHg; 2 min each step). End-tidal PO2 was clamped at 100 mmHg. CVR maps (%/mmHg) were generated by indexing the change in BOLD signal against the change in PETCO2. The percent change in brain volume was estimated and global grey and white matter volumes were calculated. Paired sample t-test and repeated measures ANOVA with Tukey’s post hoc analysis was used to identify the effect of high altitude on cerebral structure and CVR throughout anatomical regions of interest. Following return to sea level, brain volume was reduced by an estimated -0.4 ± 0.3% (p<0.01) and global volumetric analysis revealed a selective reduction in grey matter (-2.6 ± 1.0%; p<0.001) but not white matter (-1.3 ± 0.7%; p=0.14). Although global grey matter CVR (PRE: 0.31 ± 0.03; POST: 0.35 ± 0.01 %/mmHg) and white matter CVR (PRE: 0.18 ± 0.02; POST: 0.19 ± 0.01 %/mmHg) were unchanged following return to sea-level, CVR was increased in the brainstem (31 ± 12%, p<0.05), hippocampus (12 ± 3%, p<0.01), and thalamus (10 ± 3%, p<0.01). Subsequent analysis of regions of positive and negative reactivity revealed that this effect was the result of an improvement and/or reversal of negative reactivity to positive reactivity. This result was notable for grey matter, white matter, brainstem, and hippocampus. Resting minute ventilation, PETO2, PETCO2, and SpO2 were similar at baseline and follow-up. Our results indicate a loss of grey matter tissue following exposure to high altitude. In addition, we demonstrate regions of negative blood flow reactivity in healthy humans that was improved following high altitude exposure. We speculate that regional angiogenesis and/or hypoxia-induced changes in vascular CO2 sensing contribute to improved vascular function in regions of impaired cerebrovascular reactivity.