Currently there is no recognized biochemical or molecular marker for human parenchymal lung injury analogous to markers for acute myocardial injury. Injury to the alveolar epithelial barrier is of central importance in the pathogenesis of and recovery from acute lung injury. In animal models, an alveolar type I cell-specific protein, RTI(40), has been shown to be an accurate marker of alveolar epithelial damage. We now report that HTI(56), a novel apical plasma membrane protein specific to the human type I cell, is a biochemical marker for lung injury. Using a sensitive, quantitative, light-based ELISA, we measured HTI(56) in pulmonary edema fluid from 15 patients with a clinical diagnosis of acute lung injury and 12 control patients with hydrostatic (cardiogenic) pulmonary edema. HTI(56) was also measured in plasma from these two groups and from 11 normal volunteers. The amount of HTI(56) was 4. 3-fold higher (p < 0.0001) in alveolar edema fluid and 1.4-fold higher (p < 0.05) in plasma from the patients with acute lung injury, compared with patients with hydrostatic pulmonary edema. To our knowledge, this study is the first to utilize a specific marker of alveolar epithelial damage in human disease and demonstrates the feasibility of using a blood test to detect lung parenchymal damage.