Uneven hypoxic pulmonary vasoconstriction has been proposed to expose parts of the pulmonary capillary bed to high pressure and vascular injury in high-altitude pulmonary edema (HAPE). We hypothesized that subjects with a history of HAPE would demonstrate increased heterogeneity of pulmonary blood flow during hypoxia. A functional magnetic resonance imaging technique (arterial spin labeling) was used to quantify spatial pulmonary blood flow heterogeneity in three subject groups: (1) HAPE-susceptible (n = 5), individuals with a history of physician-documented HAPE; (2) HAPE-resistant (n = 6), individuals with repeated high-altitude exposure without illness; and (3) unselected (n = 6), individuals with a minimal history of altitude exposure. Data were collected in normoxia and after 5, 10, 20, and 30 minutes of normobaric hypoxia FI(O(2)) = 0.125. Relative dispersion (SD/mean) of the signal intensity was used as an index of perfusion heterogeneity. Oxygen saturation was not different between groups during hypoxia. Relative dispersion was not different between groups (HAPE-susceptible 0.94 +/- 0.05, HAPE-resistant 0.94 +/- 0.05, unselected 0.87 +/- 0.06; means +/- SEM) during normoxia, but it was increased by hypoxia in HAPE-susceptible (to 1.10 +/- 0.05 after 30 minutes, p < 0.0001) but not in HAPE-resistant (0.91 +/- 0.05) or unselected subjects (0.87 +/- 0.05). HAPE-susceptible individuals have increased pulmonary blood flow heterogeneity in acute hypoxia, consistent with uneven hypoxic pulmonary vasoconstriction.