Recent in vivo and in vitro experimental evidence indicates that transforming growth factoralpha (TGF-α) 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-α in patients with acute lung injury. Therefore, the purpose of this study was to determine if TGF-α 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-α 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-α levels were measured in 43 patients (34 with increased permeability edema, nine with hydrostatic edema). TGF-α 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-α was not detected in any plasma samples. These concentrations of TGF-α 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-α 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-α was detected so early in the course of acute lung injury.