Whole body insulin resistance has been demonstrated in septic patients and in infected animals. In this study, we demonstrate that sepsis induces insulin resistance and that pretreatment with aspirin inhibits sepsis-induced insulin resistance. Sepsis was observed to lead to serine phosphorylation of IRS-1, a phenomenon which was reversed by aspirin in muscle and WAT, in parallel with a reduction in JNK activity. In addition, our data show an impairment of insulin activation of IR and IRS-1 tyrosine phosphorylation in septic rats and, consistent with the reduction of IRS-1 serine phosphorylation observed in septic animals pretreated with aspirin, there was an increase in IRS-1 protein levels and tyrosine phosphorylation in muscle and WAT. Overall, these results provide important new insights into the mechanism of sepsis-induced insulin resistance.