Advanced liver cirrhosis is associated with hyperdynamic circulation consisting of systemic hypotension, decreased peripheral resistance and cardiac dysfunction termed cirrhotic cardiomyopathy. Previous studies have revealed the role of endocannabinoids and vascular CB₁ receptors in the development of generalized hypotension and mesenteric vasodilation in animal models of liver cirrhosis, and CB₁ receptors have been also implicated in the decreased -adrenergic responsiveness of isolated heart tissue from cirrhotic rats. Here we document the cardiac contractile dysfunction in vivo in liver cirrhosis and explore the role of the endocannabinoid system in its development. Rats with CCl₄-induced cirrhosis developed decreased cardiac contractility as documented through the use of the Millar pressure-volume microcatheter system, low blood pressure and tachycardia. Bolus i.v. injection of the CB₁ antagonist AM251 (3 mg/kg) acutely increased mean blood pressure as well as both load-dependent and -independent indices of systolic function, whereas no such changes were elicited by AM251 in control rats. Furthermore, tissue levels of the endocannabinoid anandamide increased 2.7-fold in the heart of cirrhotic compared to control rats without any change in 2-arachidonoylglycerol (2-AG) levels, whereas in the cirrhotic liver both 2-AG (6-fold) and anandamide (3.5-fold) were markedly increased. CB₁ receptor expression in the heart was unaffected by cirrhosis, as verified by Western blotting. Activation of cardiac CB₁ receptors by endogenous anandamide contributes to the reduced cardiac contractility in liver cirrhosis, and CB₁ receptor antagonists may be used to improve contractile function in cirrhotic cardiomyopathy and, possibly, in other forms of heart failure.