Sepsis remains the major cause of death in intensive care units. International guidelines for management of severe sepsis and septic shock recommend both stress-dose steroid therapy and recombinant activated protein C (APC). The aims of the present study were to compare the effects of APC and dexamethasone (Dexa) alone as well as in combination in resuscitated septic shock on survival, hemodynamics, and vascular reactivity. Sepsis was associated with a decrease in mean arterial pressure, elevation in plasma lactate and nitrite/nitrate concentration. Administration of APC, Dexa, and their combination improve arterial pressure and decrease lactate and nitrite/nitrate concentration. Both APC and Dexa improved arterial contractility and endothelial dysfunction resulting from septic shock in rats. The expression of iNOS was significantly reduced by the administration of Dexa, APC, and combination therapy. All treatments restore the Akt pathway. Moreover, their combination increased the length of survival. These findings suggest that APC and glucocorticoids should be further re-evaluated in combination in septic shock