To determine whether hypoxia directly affects pulmonary microvascular filtration of fluid or permeability to plasma proteins, we measured steady state lung lymph flow and protein transport in eight unanesthetized sheep breathing 10% O2 in N2 for 4 hours. We also studied three sheep breathing the same gas mixture for 48 hours. We surgically prepared the sheep to isolate and collect lung lymph and to measure average pulmonary arterial (Ppa) and left atrial (Pla) pressures. We placed a balloon catheter in the left atrium to elevate Pla. After recovery, the sheep breathed air through a tracheostomy for 2-4 hours, followed by 4 or 48 hours of hypoxia. In 13 4-hour studies, the average arterial PO2 fell from 97 to 38 torr; Ppa rose from 20 to 33 cm H2O; and lung lymph flow and lymph protein flow were unchanged. We also found that during 48-hour hypoxia, with a sustained elevation in Ppa and a decline in Pla, lymph flow and protein flow did not increase. In four sheep, we also raised Pla for 4 hours, followed by 4 hours of hypoxia with elevated Pla. Again, despite the added stress of elevated Pla, we found that lymph flow and lymph protein flow remained constant during hypoxia. We conclude that severe alveolar hypoxia, for 4 or 48 hours, alone or with increased pulmonary microvascular pressure, produced no change in lung fluid filtration or protein permeability, a finding supported by normal postmortem histology and extravascular lung water content.