A decrease in plasma noradrenaline—a reflection of sympathetic nervous system activity—by clonidine, a centrally acting α2-agonist, could reduce the hyperdynamic circulation observed in cirrhosis and may thereby decrease portal hypertension. Plasma noradrenaline concentration and plasma renin activity as well as systemic and splanchnic hemodynamics were measured in 12 patients with cirrhosis and ascites before and after administration of either 150 μg of clonidine or placebo. Plasma noradrenaline concentration significantly decreased in all patients after clonidine administration, whereas plasma renin activity did not change significantly. There were statistically significant reductions of cardiac output (−17.4%), mean arterial pressure (−12.2%), hepatic venous pressure gradient (−19.7%) and azygos blood flow (−26.6%) after administration of clonidine. No significant correlation was found between the reduction of plasma noradrenaline concentration and changes in systemic or splanchnic hemodynamics. Hepatic blood flow was not changed by clonidine. Placebo administration had no effect on any laboratory or hemodynamic measurement. We conclude that the reduction in sympathetic nervous system activity by clonidine and the subsequent decrease in the hyperdynamic circulation suggests that sympathetic overactivity contributes to the circulatory derangements in patients with cirrhosis.