In 45 consecutive patients referred for severe hypoxemia (Pao2 less than 100 mm Hg on positive end-expiratory pressure of 5 cm H2O and fraction of inspired O2 of 1.0), physiologic studies of gas exchange were correlated with pathologic features from 36 open lung biopsies and 15 autopsies. Three distinct groups were defined. Group 1 included 11 patients with the most severe hypoxia (Pao2, 47 +/- 12 mm Hg), minimal Pao2 response to a 10 cm H2O increase in positive end-expiratory pressure (+2.0 +/- 4.0 mm Hg), and a fixed shunt at all fractions of inspired O2. Pathologic study showed edema, exudation, and hemorrhage to the point of consolidation. In group 2 were 13 patients who had less severe hypoxia (Pao2, 60 +/- 17 mm Hg) and a moderate Pao2 response to a 10 cm H2O increase in positive end-expiratory pressure (+15 +/- 8 mm Hg), but whose maximal response was slowly achieved (30 min to several hours). Pathologic examination showed extensive fibrosis. The 21 patients in group 3 had the least hypoxia (66 +/- 15 mm Hg), and had a rapid and marked improvement in Pao2 with a 10 cm H2O increase in positive end-expiratory pressure (+68 +/- 59 mm Hg). Pathologic features were similar to but less severe than those in group 1. Venous admixture increased with decreasing inspired concentrations of O2, indicating diffusion or ventilation-perfusion abnormalities in groups 2 and 3. Prognosis was best for group 3, with 10 of 21 long-term survivors. Two of 11 group 1 patients survived, but only after prolonged periods of extracorporeal membrane oxygenation. Despite biopsy evidence of extensive fibrosis, 3 of 13 in group 2 survived with moderate to good pulmonary function, including 1 survivor who had had extracorporeal membrane oxygenation. Such combined physiologic and pathologic studies are useful (1) for optimal respiratory care, (2) for prognosis, (3) for development of indications for extracorporeal membrane oxygenation, and (4) for better understanding of the pathophysiology of adult respiratory distress syndrome.