Plasma vasoactive intestinal polypeptide (VIP) increased significantly in the portal vein, the superior caval vein, the internal jugular vein, and the aorta during an intravenous infusion of E. coli endotoxin in six anesthetized pigs, which all developed a deep shock, with fall in aortic blood pressure and urinary output. Plasma VIP peaked simultaneously with the most pronounced shock symptoms, and the level in the portal vein was significantly higher than in blood from the other sampling sites. In contrast, no significant change in plasma secretin was noted. It is suggested that the gastrointestinal tract is the main source of the high plasma VIP levels seen during endotoxinemia and that VIP may play a significant role in endotoxin shock.