The activities of 2 peptidases, angiotensin-I converting enzyme (ACE) and neutral metalloendopeptidase (NEP), were measured in serum from patients with adult respiratory distress syndrome (ARDS). As noted by others, we found that the specific activity of serum ACE was reduced in patients with severe alveolocapillary damage caused by ARDS. In addition, patients who were severely ill with chronic obstructive lung disease had lower serum ACE than did normal ambulatory control subjects. Patients with cardiogenic pulmonary edema, however, had no consistent loss of the enzyme. The most striking changes occurred in the serum levels of NEP. Whereas the specific activity of this enzyme was very low in the normal subjects, it was elevated as much as 50- to 60-fold in serum samples from patients with ARDS. Serum from patients with cardiogenic pulmonary edema had high levels of NEP, and it was elevated also in a subset of patients with chronic obstructive lung disease. On the assumption that patients with ARDS sustain significant damage at the alveolar-capillary level, these changes in ACE and NEP could signal endothelial damage; ACE loss could result from direct injury to the vascular lumen, and NEP from subendothelial tissues could enter the bloodstream through damaged endothelium. Alternatively, NEP might be released from leukocytes sequestered in the lung and leak into the bloodstream.