Although heme is necessary in many life-sustaining functions, its overwhelming systemic release with rhabdomyolysis (RM) is believed to be the cause of subsequent organ injury and dysfunction. We investigated the acute effects of experimental RM on hepatic parenchymal viability and microvascular function in vivo, while also determining the impact of cobalt protoporphyrin (CoPP) on its outcome. With a murine model of RM induced by hind limb glycerol administration (11.5 microL/g, i.m.), we show that plasma heme is elevated as early as 30 min after hind limb glycerol. However, significant hepatic heme accumulation did not occur until 3 h later, with a return to basal levels by 6 h. Using in vivo digital microscopy, hepatic parenchymal viability and microvascular function were found to be significantly compromised by 3 h of RM. Moreover, this response included the upregulation of hepatic heme oxygenase protein expression and activity. The administration of CoPP (5 mg/kg, i.p.) protected hepatic parenchymal and microvascular integrity in the face of the RM insult. This hepatoprotection appears to involve the rapid degradation of heme by heme oxygenase, with subsequent alterations in hepatic microvascular resistance and heme accumulation. The evidence from this investigation suggests that RM mediates a detrimental response in the hepatic parenchyma and microcirculation, and that these responses can be mediated by the rapid degradation of hepatic heme via CoPP-induced heme oxygenase activity.