Basal plasma concentrations of human pancreatic polypeptide (PP) were measured in 14 patients with chronic renal failure (CRF), 13 patients with cirrhosis of the liver, and age-matched controls. PP was significantly higher in patients with CRF than in controls (817 +/- 183 vs. 157 +/- 118 pg/ml; P < 0.005). The degree of PP elevation in patients with CRF correlated well with the degree of their renal insufficiency (r = 0.85; P < 0.001). Fractionation of plasma over Sephadex G-50 columns revealed comparable elution patterns in patients with CRF and in normal controls. Hemodialysis had no effect on the PP concentration. We also determined arterial venous PP concentration differences and plasma blood flow across the kidneys and liver in 13 patients with cirrhosis and arteriovenous differences across of the liver in 13 controls with normal hepatic and renal functions. The mean PP concentration was significantly higher in arterial plasma than in renal venous plasma (143 +/- 24 vs. 123 +/- 23 pg/ml; P < 0.025). Renal fractional extraction was 17.2 +/- 6.6%, and renal clearance of PP was 151 +/- 47 ml/min. No significant extraction of PP occurred across the liver. It is concluded that the kidneys, but not the liver, are important sites for the metabolism of PP and that elevated PP concentrations in patients with CRF may contribute to their uremic syndrome.