Gel filtration of plasma from normal subjects and patients with chronic renal failure (CRF) yielded four immunoreactive human pancreatic polypeptide (IRhPP) peaks of approximately greater than 20,000, 10,000, 4200, and 2000 daltons. In normal subjects, the basal plasma distribution was 36 +/- 2%, 16 +/- 3%, 25 +/- 1% and 23 +/- 2%, respectively. In the CRF patients, the total plasma IRhPP was close to ten times higher than in the normal group. This difference was due to an increase in IRhPP10000 and IRhPP4200 plasma levels. After a standard breakfast, plasma IRhPP10000 and IRhPP4200 levels increased in the normal subjects and in the CRF patients, while the levels of the other two plasma components were not affected by the meal. In a patient with multiple endocrine adenomatosis type 1, the basal plasma levels of IRhPP10000 and IRhPP4200 were, respectively, 41 and 44 times higher than the mean value in the normal subjects; these fractions appeared to be further increased after breakfast. In trying to characterize the IRhPP10000, it was found that treatment with urea, guanadium hydrochloride, and acetic acid (pH 2.2) did not alter its molecular size, whereas limited trypsin treatment was able to destroy part of the immunoreactivity and to produce greater than 20,000-dalton and 4200-dalton immunoreactive materials. Plasma IRhPP10000 seems to be a co-secretory product of the PP cell, and the kidney plays a role in its catabolism as well as in that of the IRhPP4200 component. The IRhPP10000 component may correspond to a PP precursor.