The significance of hyperamylasemia and its relationship to pancreatitis after cardiac surgery is controversial. Three hundred consecutive patients undergoing cardiopulmonary bypass were prospectively studied to determine the incidence and significance of postoperative hyperamylasemia. Ninety-six of three hundred patients (32%) developed hyperamylasemia. Fifty-six patients (19%) were classified as having isolated hyperamylasemia because they were asymptomatic and had normal serum lipase. Thirty-two patients (10.7%) had subclinical pancreatitis defined as elevation of serum amylase and lipase or pancreatic isoamylase. Many of these patients had mild gastrointestinal symptoms that were self-limited. Eight patients (2.7%) had overt pancreatitis documented by clinical findings, biochemical abnormalities, and computed tomography (CT) scan or autopsy. Isoamylase analysis demonstrated that isolated hyperamylasemia usually originated from nonpancreatic sources. However, hyperamylasemia occurring in conjunction with abdominal signs and symptoms or elevated serum lipase was almost always pancreatic in origin. Patients with hyperamylasemia had a significantly higher mortality rate (seven of 96 patients, 7.5%) than those with normal serum amylase (two of 204 patients, 0.9%) (p less than 0.01) even when the amylase was nonpancreatic in origin (five of 56 patients, 9%). The reason that nonpancreatic hyperamylasemia is associated with increased postoperative mortality is not established but may represent a variety of metabolic aberrations or tissue injuries. It is concluded that 1) hyperamylasemia after cardiopulmonary bypass is a marker of potential clinical importance, and 2) pancreatitis in this setting is more common than previously recognized and is a potentially lethal complications. Successful treatment depends on early diagnosis and aggressive treatment.