Rationale: Inhomogeneous hypoxic pulmonary vasoconstriction causing regional overperfusion and high capillary pressure is postulated for explaining how high pulmonary artery pressure leads to high altitude pulmonary edema in susceptible individuals (HAPE-S). Objective: Since different species of animals also show inhomogeneous hypoxic pulmonary vasoconstriction, we hypothesized that inhomogeneity of lung perfusion in general increases in hypoxia, but more pronounced in HAPE-S. For best temporal and spatial resolution regional pulmonary perfusion was assessed by dynamic contrast-enhanced-magnetic resonance imaging. Methods: Dynamic contrast-enhanced magnetic resonance imaging and echocardiography were performed during normoxia and after 2 hours of hypoxia (FIO2=0.12) in 11 HAPE-S and 10 controls. As a measure for perfusion inhomogeneity the coefficient of variation for two perfusion parameters (peak signal intensity, time-to-peak) was determined for the whole lung and isogravitational slices. Results: There were no differences in perfusion inhomogeneity between the groups in normoxia. In hypoxia analysis of coefficients of variation indicated a greater inhomogeneity in all subjects which was more pronounced in HAPE-S compared to controls. Discrimination between HAPE-S and controls was best in gravity dependent lung areas. Pulmonary artery pressure during hypoxia increased from 22±3 to 53±9 mmHg in HAPE-S and 24±4 to 33±6 mmHg in controls (mean±SD, p<0.001), respectively. Conclusion: This study shows that hypoxic pulmonary vasoconstriction is inhomogeneous in hypoxia in humans, particularly in HAPE-S where it is accompanied by a greater increase in pulmonary artery pressure compared to controls. These findings support the hypothesis of exaggerated and uneven hypoxic pulmonary vasoconstriction in HAPE-S.