Patients who undergo cardiopulmonary bypass experience derangements of complement activation, prostaglandin metabolism, and catecholamine secretion, which have all been posited to explain postoperative fluid retention and paroxysmal hypertension. Atrial natriuretic factor, a hormonal peptide released by the cardiac atria, regulates vascular volume by increasing sodium excretion and decreasing vasomotor tone and catecholamine synthesis. We examined its possible response to cardiopulmonary bypass in 23 patients (18 having cardiopulmonary bypass and, as a control group, five having thoracotomy) who underwent serial blood sampling to measure plasma atrial natriuretic factor levels before, during, and after operation. Thoracotomy alone had no effect on atrial natriuretic factor levels before, during, and after operation. Patients with cardiac valve lesions who had a higher incidence of arrhythmias and congestive heart failure showed elevated preoperative atrial natriuretic factor values (p less than 0.05). Normally, atrial natriuretic factor release is directly related to atrial filling pressure, but all patients having cardiopulmonary bypass revealed a paradoxical rise of atrial natriuretic factor during cardiopulmonary bypass (p less than 0.01) and a lack of correlation between atrial filling pressure and atrial natriuretic factor secretion in the early postoperative period. The atrial natriuretic factor response to pulmonary wedge pressure began to normalize 24 hours after operation. The unique reaction of this recently discovered cardiac hormone to cardiopulmonary bypass suggests its possible role in the pathophysiologic response to cardiac operation.