Heme oxygenase 1 (HO-1) enhances cellular antioxidative capability by increasing the cleavage of the endogenous and exogenous heme. Besides the biochemical activities of HO, the products of heme degradation significantly contribute to the cytoprotective effects of HO. Here, we show that HO-1 deficiency significantly increases the susceptibility of mice to apoptotic insults, whereas expression of HO-1 significantly increased the resistance of primary hepatocyte to apoptosis. This phenomenon was correlated with the production of one of its catalytic products-carbon monoxide (CO). Surprisingly, exposing the primary mouse hepatocyte to CO could improve the cellular energy metabolism in a soluble guanylyl cyclase-dependent manner. One-hour inhalation of low-dose CO enhanced the hepatic soluble guanylyl cyclase activities in mice. In parallel, the levels of hepatic adenosine triphosphate increased significantly and were associated with a marked reduction of TNF-α-induced apoptosis in the liver of D-galactosamine-sensitized mice. In addition, CO inhalation for 1 h significantly improved the survival of mice after initiation of fulminant hepatitis. Up to 90% of mice given CO survived for more than 7 days, whereas control mice died within 12 h. The data provide novel insight of CO-mediated cytoprotection.