Objective: Nonsteroidal antiinflammatory drugs appear to improve insulin sensitivity and are currently tested in clinical trials. Salsalate, however, may blunt mitochondrial function, an unwarranted side effect for type 2 diabetics. We examined the effect of salsalate on ex vivo mitochondrial function and lipid-induced insulin resistance. Design: In a crossover design, nine volunteers underwent a hyperinsulinemic-euglycemic clamp with simultaneous infusion of glycerol (control), Intralipid, or Intralipid preceded by 4 d of salsalate (4000 mg Disalsid). Oxidative glucose disposal and nonoxidative glucose disposal (NOGD), metabolic flexibility, energy expenditure (EE), and ex vivo muscle mitochondrial function were measured. Results: Lipid infusion reduced insulin-stimulated glucose disposal by approximately 40%, glucose oxidation (CHOox) by approximately 50%, and NOGD by approximately 35%. Lipid-induced whole-body insulin resistance and decreased NOGD were not ameliorated by salsalate. However, salsalate repressed lipid-induced reduction in CHOox and reduced insulin clearance, resulting in higher insulin levels under basal as well as under clamp conditions (~25 and ~39%, respectively). Intriguingly, EE was higher after administration of salsalate (~18 and ~16% under basal and clamp conditions, respectively) and was fueled by increased fat oxidation in the basal state and increased CHOox upon insulin stimulation. Salsalate did not affect mitochondrial function and coupling. Conclusion: We conclude that salsalate failed to improve whole-body insulin sensitivity but increased basal fat oxidation and insulin-stimulated CHOox, indicating improved metabolic flexibility. The beneficial effects of salsalate on CHOox can be attributed to elevated insulin levels. Mitochondrial respirometry revealed no indications that the changes in substrate selection and EE could be attributed to changes in skeletal muscle mitochondrial capacity or mitochondrial coupling.