We have previously reported, in patients with acute respiratory distress syndrome (ARDS), elevated plasma levels of vascular endothelial growth factor (VEGF) that became reduced in those who recovered. To examine the potential effect of VEGF on the epithelial side of the alveolar-capillary membrane, we compared VEGF levels in the epithelial lining fluid (ELF) of the same 40 patients with ARDS, and in 28 patients at risk of ARDS. We measured intrapulmonary VEGF levels in 23 patients on Days 1 and 4 after admission to the intensive therapy unit and related these levels to recovery. ELF from subjects with ARDS contained lower levels of VEGF than did ELF from at-risk subjects (1,076 and 7,674 pg/ml, respectively, p = 0.0004) and increased ELF levels at Day 4 were associated with recovery (p = 0.001). Alveolar macrophages from subjects with ARDS produced significantly less VEGF than those from at-risk subjects (6.3 and 13.0 pg/ml, respectively, p = 0.005). Similarly, alveolar neutrophils from subjects with ARDS produced significantly less VEGF than those at risk (13.9 and 31.5 pg/ml, respectively, p = 0.03). ELF VEGF levels inversely correlated with Lung Injury Score (p = 0.003). These studies suggest that VEGF in the alveolar space may reflect the development of, and recovery from, acute lung injury in a manner opposite to that in plasma.