BACKGROUND Plasma peptide YY (PYY) levels rise after a meal and have recently been shown to increase small bowel-absorption. The purpose of this study was to determine whether immunoneutralization of PYY would block postprandial absorption in vivo. METHODS Exteriorized, neurovascularly intact jejunal and ileal segments (25 cm) were created in six mongrel dogs. After a 2-week recovery luminal perfusion with an isotonic buffer, containing [14C]-polyethylene glycol as a volume marker, was used to analyze water and sodium flux after an oral meal. Each meal was accompanied by either intravenous anti-PYY (0.5 mg.kg-1.h-1) or nonspecific immunoglobulin IG (control). PYY antibody binding was determined by radioimmunoassay. RESULTS Displacement studies showed complete PYY neutralization. In control experiments feeding increased absorption of sodium and water in both segments. PYY immunoneutralization had no effect on jejunal absorption but significantly diminished ileal absorption (p < 0.05). CONCLUSIONS These results suggest that PYY acts selectively in the ileum to increase postprandial fluid and electrolyte absorption after a meal. Agents directed at PYY-stimulated absorption may prove to be of therapeutic benefit in patients with malabsorptive conditions.