Surfactant protein-A (SP-A) leaks into the circulation of patients with acute respiratory distress syndrome (ARDS) or acute cardiogenic pulmonary edema (APE) in a manner inversely related to lung function. Since surfactant protein-B (SP-B) is synthesized as a precursor considerably smaller than alveolar SP-A, we investigated whether it enters the circulation more readily. Reactivities consistent with SP-B proprotein (approximately 42 to approximately 45 kD) and the approximately 25 kD processing intermediate were detected in plasma. Plasma immunoreactive SP-B levels were significantly higher in ARDS (8,007+/-1,654 ng/ml [mean+/-SEM], n = 22) and APE (3,646+/-635 ng/ml, n = 10) patients compared with normal subjects (1,685+/-58 ng/ml, n = 33) and ventilated patients with no cardiorespiratory disease (1,829+/-184 ng/ml, n = 7). All groups had plasma SP-B/SP-A ratios approximately 6- to approximately 8-fold higher than in normal lavage or ARDS tracheal aspirate fluid, consistent with protein sieving. During admission, both plasma SP-B and the SP-B/SP-A ratio were inversely related to blood oxygenation (PaO2/FIO2) (p < 0.0001 and p < 0.025, n = 260 from 39 patients; Spearman) and static respiratory system compliance (deltaV/deltaP) (p < 0.0001 and p < 0.01, n = 168 from 25 patients). We describe in detail three patients and conclude that immunoreactive SP-B enters more readily than SP-A, is cleared acutely, and provides a better indicator of lung trauma.