The etiology of the hyperkinetic circulatory state in cirrhosis is equivocal and reduced peripheral vascular resistance is a major unsolved problem in hepatic pathophysiology. It is therefore sensible to search for vasodilators. A recently discovered neuropeptide, calcitonin gene-related peptide (CGRP), is a highly potent vasodilator. We determined the circulating concentration of immunoreactive CGRP in different vascular beds in 35 patients with cirrhosis and in eight patients with minor disorders. Plasma CGRP was significantly increased in the cirrhotic patients compared with patients with minor disorders (59 vs. 46 pmol/l, p less than 0.01), as well as with 232 healthy persons (37 pmol/l, p less than 0.0001). Moreover, circulating CGRP increased significantly with the severity of cirrhosis (Child-Turcotte group A, 56; group B, 59; group C, 71 pmol/l; p less than 0.025). No significant arterio-venous net extraction or release of CGRP was found across the hepato-intestinal system, kidney, lung or limb. In conclusion, elevated circulating CGRP may play a role in the haemodynamic derangement of cirrhosis. The lack of organ arterio-venous differences suggests a widespread release and degradation of CGRP in many tissues and gives no evidence of decreased degradation as the cause of increased plasma CGRP in patients with cirrhosis.