Hyperglycemia and insulin resistance have long been recognized in severe burn patients. Early excision and grafting reduces cytokines and insulin resistance in burned rats. The authors hypothesized that early wound excision and grafting in patients would also reduce insulin resistance induced by major burn. Thirty-five adult surviving major burn patients (>40%TBSA burn) were recruited. The removal of dead devitalized tissue and allografting in escharectomy group was performed within 72 hours and in control group about 7 days after burn injury. The concentrations of plasma insulin, glucose, and cytokines were measured at 2 and 5 days postburn. Euglycemic-hyperinsulinemic glucose clamps were performed at 5 days after burn. The levels of phosphotyrosine, phosphoserine³¹² of insulin receptor substrate (IRS)-1, and phospho-jun N-terminal kinase (JNK) in muscle were analyzed with immunoprecipitation and Western blotting at 5 days postburn. Escharectomy and allografting during shock stage significantly reduced the levels of interleukin-6 and tumor necrosis factor-α, decreased the levels of phosphoserine³¹² and phospho-JNK, increased the level of phosphotyrosine of IRS-1, and further reduced insulin resistance at 5 days after thermal injury compared with delayed excision group. Escharectomy and allografting during shock stage seemed to have an immunomodulatory effect on the inflammatory mediators and further to reduce insulin resistance induced by major burns in patients by decreasing the phosphorylation of IRS-1 serine³¹² and JNK1/2.