Nitric oxide and atrial natriuretic peptides are the main activators of guanylyl cyclases, which transform ITP into cyclic GMP and thereby contribute to the decrease of vascular tone. To investigate the increase, if any, of plasma cyclic GMP concentrations in human patients with hyperdynamic circulation resulting from acute liver failure and to ascertain whether guanylyl cyclase activation is involved in the decline of systemic vascular resistance that occurs in this pathophysiological condition, we simultaneously recorded hemodynamic data and cyclic GMP levels in patients with fulminant liver failure before and after liver transplantation and in normokinetic patients undergoing abdominal nonseptic surgery. We also compared these data with those recorded in patients with hyperkinetic shock resulting from gram-negative sepsis or nitric oxide-independent vasomotor agent (carbamate) overdose. In all these patients we simultaneously studied kidney function, platelet counts and atrial natriuretic peptides. Patients with fulminant liver failure had higher cyclic GMP concentrations than did control patients undergoing abdominal surgery (11.02 ± 1.55 pmol·ml−1 vs. 1.77 ± 0.18 pmol · ml−1, P < 0.001). At similar heart-loading conditions these concentrations were lower than those in gram-negative septic shock (18.2 ± 1.35 pmol·ml−1, p < 0.05) but higher than those in carbamate-induced shock (3.6 ± 0.7 pmol·ml−1, p < 0.01). In addition, cyclic GMP concentrations significantly decreased from the fulminant liver failure period to the posttransplantation period, although atrial natriuretic peptide levels did not change significantly and kidney function worsened. During the period of fulminant liver failure, cyclic GMP levels correlated with the decline in peripheral resistance but not with other hemodynamic or biological data. With the improvement of peripheral resistance after the transplantation procedure, they did not further correlate with systemic vascular resistance, only with creatininemia. Together these results suggest that guanylyl cyclase activation is involved in the low vascular resistance observed during acute hepatocellular syndrome; furthermore, they indicate that particulate guanylyl cyclase activation only partially explains the increase in cyclic GMP observed during fulminant liver failure and put forward a role for soluble guanylyl cyclase activators such as nitric oxide. (Hepatology 1994;19;38–44).