The influence of PEEP during controlled mechanical ventilation (CMV) on plasma levels of alpha-atrial natriuretic peptide (alpha-ANP) was examined in seven patients suffering from acute respiratory failure. The majority of patients were volume-expanded. Samples were drawn from the superior vena cava, right atrium, pulmonary artery, and radial artery. All alpha-ANP levels were significantly depressed by 15 cm H2O PEEP for one hour, when compared to CMV without PEEP. During the PEEP period, cardiac index, creatinine clearance, urinary flow and urinary sodium excretion were decreased. CMV with PEEP of 20 cm H2O depressed peripheral venous plasma levels of alpha-ANP in six volume-expanded healthy volunteers, too. The decreased release of alpha-ANP could be a consequence of atrial compression by the distended lungs and of reduced venous return. We suggest that the decline in plasma alpha-ANP levels contributes to fluid retention and renal dysfunction, which occur frequently during CMV with PEEP. More detailed studies are necessary to confirm our hypothesis.