The concentration of vasoactive intestinal polypeptide (VIP) was determined in peripheral venous plasma from 136 patients with liver cirrhosis without gastrointestinal bleeding or coma and from 112 controls. In eight patients (cirrhosis, six; fibrosis, one; steatosis, one) arteriovenous extraction or release of VIP was measured during catheterization at four locations: brain, lower limb, intestine-liver, and kidney. The mean concentration of VIP in peripheral venous plasma from patients with cirrhosis was 9.4 pmol/l (median, 7.0; range, 0-86), which was significantly higher than that of the controls, who had a mean of 6.2 pmol/l (median, 6.0; range, 0-20, P less than 0.01). No significant extraction or release of VIP could be detected across the vascular bed in brain or lower limb. A significant arterio-hepatovenous VIP extraction ratio (mean, 0.43; range, 0.05-0.87) confirmed at net splanchnic elimination of VIP from extra-splanchnic areas and from porto-systemic shunting of VIP in cirrhosis. The net splanchnic elimination rate of VIP was estimated to be about 3 pmol/min. The concentration of VIP in ascitic fluid was on the average three times that of arterial plasma. In conclusion, VIP is significantly elevated in peripheral plasma from patients with cirrhosis, probably due to porto-systemic shunting and/or compromised hepatic elimination. Hepatic elimination is still likely to account for the inactivation of most of the VIP escaping from the neurosynapses throughout the body in patients with cirrhosis without coma.