Recent in vivo and in vitro experimental evidence indicates that transforming growth factor-alpha (TGF-alpha) is an important growth factor in the process of recovery and remodeling that occurs after acute lung injury. However, there are very little clinical data on TGF-alpha in patients with acute lung injury. Therefore, the purpose of this study was to determine if TGF-alpha is present in biologically significant concentrations in the pulmonary edema fluid from patients with acute lung injury, and to determine if the presence of TGF-alpha is specific for acute lung injury by including control patients with hydrostatic edema. Using an enzyme-linked immunosorbent assay, plasma and pulmonary edema fluid TGF-alpha levels were measured in 43 patients (34 with increased permeability edema, nine with hydrostatic edema). TGF-alpha was detected in 24 of 34 patients (71%) with increased permeability pulmonary edema (range, 0.035 to 2.57 ng/mL) compared with only two of nine patients with hydrostatic edema (p < 0.05). TGF-alpha was not detected in any plasma samples. These concentrations of TGF-alpha in pulmonary edema fluid have potent in vivo and in vitro effects on alveolar epithelial sodium transport and alveolar epithelial cell motility. In conclusion, biologically relevant concentrations of soluble TGF-alpha are present in the pulmonary edema fluid on day 1 of patients with acute lung injury, a remarkable finding with important implications for the repair and resolution of acute lung injury, particularly since TGF-alpha was detected so early in the course of acute lung injury.