Recent evidence indicates that inflammatory pathways are causally involved in insulin resistance. In particular, Iκ Bα kinase β (IKKβ ), which can impair insulin signaling directly via serine phosphorylation of insulin receptor substrates (IRS) and/or indirectly via induction of transcription of proinflammatory mediators, has been implicated in free fatty acid (FFA)-induced insulin resistance in skeletal muscle. However, it is unclear whether liver IKKβ activation plays a causal role in hepatic insulin resistance caused by acutely elevated FFA. In the present study, we wished to test the hypothesis that sodium salicylate, which inhibits IKKβ , prevents hepatic insulin resistance caused by short-term elevation of FFA. To do this, overnight-fasted Wistar rats were subject to 7-h i.v. infusion of either saline or Intralipid plus 20 U/ml heparin (IH; triglyceride emulsion that elevates FFA levels in vivo ) with or without salicylate. Hyperinsulinemic–euglycemic clamp with tracer infusion was performed to assess insulin-induced stimulation of peripheral glucose utilization and suppression of endogenous glucose production (EGP). Infusion of IH markedly decreased ( P < 0.05) insulin-induced stimulation of peripheral glucose utilization and suppression of EGP, which were completely prevented by salicylate co-infusion. Furthermore, salicylate reversed IH-induced 1) decrease in Iκ Bα content; 2) increase in serine phosphorylation of IRS-1 (Ser 307) and IRS-2 (Ser 233); 3) decrease in tyrosine phosphorylation of IRS-1 and IRS-2; and 4) decrease in serine 473-phosphorylated Akt in the liver. These results demonstrate that inhibition of IKKβ prevents FFA-induced impairment of hepatic insulin signaling, thus implicating IKKβ as a causal mediator of hepatic insulin resistance caused by acutely elevated plasma FFA.