Seventeen patients with chronic hyperamylasemia were studied using standard clinical and laboratory parameters, amylase/creatinine clearance ratios, and polyacrylamide gel electrophoresis of serum amylases. These patients, none of whom had evidence of pancreatic disease or other specific source for the elevated serum amylase, fell into three groups: (1) Normal serum isoamylase profile and normal amylase clearance (6 patients). We postulate that the generalized hyperamylasemia may be due to reduced extrarenal catabolism of amylase, a previously undescribed phenomenon. (2) Macroamylasemia and very low amylase clearance (9 patients). Seven of the nine patients had recurrent epigastric pain. Evidence for an autoimmune basis is discussed. (3) Salivary-type hyperamylasemia and low amylase clearance (2 patients). This entity may really be macroamylasemia in which the macroamylase complex dissociated during analysis. Chronic hyperamylasemia is often not of pancreatic origin. The assumption that the pancreas is at fault, especially if there is abdominal pain, may cause morbidity due to gross overtreatment.