Many patients who experience surgical stress including burn injury, become susceptible to severe sepsis and septic organ dysfunction, which remains the primary contributor to morbidity and mortality in burn patients. In the present study, we developed a murine model of burn-primed sublethal endotoxemia by producing a 15%BSA full-thickness burn on the dorsum of BALB/c mice under ether anesthesia and administering 10 mg/kg LPS intravenously on day 11 to model endotoxemia. The prior burn injury in this model induced two-peaked production of cytokines, TNF-alpha and MIP-2, at 2 and 12 hours after LPS administration, and it was associated with increased mortality. We also assessed the effect of pharmacological modulation with cytokine synthesis inhibitors, prednisolone and JTE-607, and found that pretreatment with them attenuated later cytokine production and decreased mortality after LPS administration. We speculate that the prior burn injury primed the mice for the secondary insult via cytokine production. These results also suggested that an anti-cytokine strategy might serve as a novel prophylactic therapy for septic organ dysfunction in burn-primed patients.