Circulating angiopoietin (Ang) 1 may inhibit and Ang-2 may enhance pulmonary vascular permeability in septic and nonseptic patients with or at risk for acute lung injury or acute respiratory distress syndrome. We hypothesized that the soluble form of the Ang-binding Tie2 receptor (sTie2), whose shedding may be induced by vascular endothelial growth factor (VEGF) levels, may bind circulating Angs and thereby inhibit their effects on pulmonary vascular permeability. In 24 septic and 40 nonseptic mechanically ventilated patients, sTie2, Ang-1, Ang-2, and VEGF plasma levels were measured together with the pulmonary leak index (PLI) for 67 Gallium-labeled transferrin as a measure of pulmonary vascular permeability. Soluble Tie2 and VEGF levels correlated (r= 0.53, P= 0.001). Soluble Tie2 was higher in septic than in nonseptic patients (7.43 [6.57-8.40] vs. 5.03 [4.57-5.54] ng/mL; P< 0.001). Soluble Tie2 was associated with the PLI (standardized regression coefficient [β]= 0.26; P= 0.006) but lost its association with the PLI when the Angs were included in a multivariate model. Soluble Tie2 did not affect the association between Ang-1 or Ang-2 and the PLI (β=− 0.39, P< 0.001; β= 0.52, P< 0.001, respectively), independently of underlying disease. Although limited to correlations and associations, the clinical data support in vivo shedding of sTie2 through VEGF signaling upon pulmonary vascular injury. However, this shedding may not prevent a direct role of Angs in pulmonary vascular permeability.