Prolonged hypoxia causes several adaptive changes in systemic physiology and tissue metabolism. We studied the effects of hypobaric hypoxia on glucose transport at the blood-brain barrier (BBB) in the rat. We found that hypoxia increased the density of brain microvessels seen on immunocytochemical stains using an antibody to the glucose transporting protein GLUT. In addition, we found that hypoxia increased the density of GLUT in isolated cerebral microvessels as determined by specific cytochalasin B binding. The higher GLUT density in isolated cerebral microvessels was evident after 1 wk of hypoxia and was associated with decreased activity of gamma-glutamyltranspeptidase. Consistent with these findings, we also demonstrated that 3 wk of hypobaric hypoxia caused increased unidirectional transport of glucose at the BBB in several brain regions in vivo, as determined by the doubly labeled single-pass indicator-fractionation atrial bolus injection method in anesthetized rats. We conclude that chronic hypobaric hypoxia is associated with increased glucose transport at the BBB.