Circulating human pancreatic polypeptide (hPP) concentrations in the plasma of 61 patients were determined by radioimmunoassay and compared with concentrations in normal age-matched subjects to assess the role of plasma hPP in diagnosis and detection of pathologic dysplasias in endocrinopathies. Basal fasting plasma hPP concentrations greater than 3.0 times normal values were found in six of six patients with multiple endocrine adenopathy syndrome, type I (MEA I) who had islet cell tumors that contained hPP and in only three of 15 nonfamilial patients with sporadic islet cell tumors. An exaggerated plasma hPP response to meal stimulation that exceeded greater than 4.5 times the basal value was found in 15 of 18 patients with MEA I, which indicated the presence of endocrine cell hyperplasia as the underlying genetic trait. The abnormal plasma hPP response to meal stimulation correlated most strongly with islet cell hyperplasia in both the genetic and sporadic endocrinopathies and to some extent with antral G cell hyperplasia. In patients with primary hyperparathyroidism, an exaggerated plasma hPP response to meal stimulation is highly indicative of genetic parathyroid hyperplasia in MEA I and not of sporadic parathyroid adenoma. Informed consent was obtained from all patients who were subjects of these investigations.