Infusion of vasoactive intestinal polypeptide (VIP) is known to cause intestinal secretion in animal models. The present study was designed to answer the question whether VIP has a similar effect on the human intestine. Pure porcine VIP was administered by constant i.v. infusion to healthy subjects while their jejunum was perfused with a plasma-like electrolyte solution. At the lowest VIP infusion rate (100 pmol/kg/hr), plasma VIP levels rose two- to four-fold, and there was an increase in the transmucosal potential difference but no change in sodium chloride absorption. At higher VIP infusion rates (200 and 400 pmol/kg/hr), VIP plasma concentrations rose to levels commonly observed in patients with pancreatic cholera syndrome. At these levels VIP caused a dose-dependent decrease of water and sodium absorption. Chloride absorption changed to secretion, while bicarbonate movement remained completely unaffected. Chloride secretion was active, since it occurred against an electrical and chemical gradient. All changes induced by VIP were reversible after discontinuance of VIP infusion. Our observations suggest that elevated levels of circulating VIP are capable of affecting water and ion movement in the human jejunum. They lend support to the hypothesis that high levels of circulating VIP may be a mediator of secretory diarrhea in some patients with pancreatic cholera syndrome.