This study investigated the short-term effects of ritanserin, a selective and specific S2-serotonergic antagonist, in an experimental model of cirrhosis and intrahepatic portal hypertension caused by long-term bile duct ligation and division and in normal control rats. The rats subjected to bile duct ligation were randomized under blind conditions into two groups to receive ritanserin (0.7 mg/kg body wt, intravenously; n = 10) or the same volume of placebo (isotonic saline solution; n = 10). We performed hemodynamic studies with radiolabeled microspheres 60 min after drug administration. Two groups of normal rats (n = 6) were studied after they received ritanserin or placebo. Ritanserin administration to rats subjected to bile duct ligation significantly reduced portal pressure (from 16.2 ± 1.3 mm Hg to 12.3 ± 0.7 mm Hg; mean decrease, 22% ± 5%; p < 0.05). This reduction was associated with lower portal venous resistance (4.3 ± 0.5 mm Hg ± min. 100 gm/ml in the placebo group vs. 3.1 ± 0.3 mm Hg. min. 100 gm/ml in rats given ritanserin; mean decrease, 28%; p = 0.069), but we saw no changes in portal vein inflow (3.9 ± 0.5 ml/min ± 100 gm vs. 4.4 ± 0.4 ml/min ± 100 gm), mean arterial pressure (110 ± 9 mm Hg vs. 102 ± 9 mm Hg) and cardiac index (32.9 ± 2.7 ml/min ± 100 gm vs. 40.5 ± 6.7 ml/min ± 100 gm). Hepatic arterial and kidney blood flows were not modified by ritanserin. Ritanserin had no systemic or splanchnic effects in normal rats. Our results demonstrate that ritanserin infusion decreases portal pressure without any systemic hemodynamic change in rats with secondary biliary cirrhosis and portal hypertension. These findings provide further support for a role of serotonin in the pathogenesis of portal hypertension and suggest a potential use of ritanserin (alone or associated with other agents) in the pharmacological treatment of portal hypertension. (HEPATOLOGY 1993;18:389–393).