Prolonged hemorrhagic shock is characterized by the progression from hyperglycemia to hypoglycemia and failure to respond to standard methods of resuscitation. Previous studies have shown that the transition to irreversible shock is accompanied by attenuation of hepatic gluconeogenic capacity and a rising level of intracellular calcium. Additionally, it has been observed that diltiazem improves survival following prolonged hemorrhagic shock in rats. We examined the effect of resuscitation containing diltiazem upon hepatic gluconeogenesis during early and late phases of hemorrhagic shock in a rat model. Fasted male Sprague-Dawley rats (250–350 g) were rapidly bled to a mean arterial pressure of 40 mm Hg for a period of 30 minutes (group A) or 120 minutes (group B). At the end of the hemorrhagic shock period, rats were randomized to resuscitation utilizing lactated Ringer's (LR) solution, or LR + diltiazem (DZ, 1.2 mg/kg). Following resuscitation, rats underwent laparotomy and in situ liver perfusion with an oxygenated 37°C glucose-free Krebs solution via the portal vein. After equilibration, 5 mmol/L lactate and 0.5 mmol/L pyruvate were added to the perfusate as substrate and effluent samples collected. Serum glucose concentration and portal venous flow did not differ significantly between DZ and LR groups throughout the study periods. In group A, hepatic glucose production was significantly elevated in DZ animals when compared with controls (p< 0.05). A similar significant improvement in gluconeogenesis was observed following 120 minutes of hemorrhagic shock in group B (p< 0.05). Additionally, treated rats (DZ, both groups A and B) demonstrated improved gluoneogenic response to substrate when compared with controls. Hemorrhagic shock is associated with attenuation of hepatic gluconeogenesis in response to substrate. The addition of diltiazem to standard LR resuscitation restores hepatic gluconeogenic response following hemorrhagic shock.