PPARα is a ligand-dependent transcription factor expressed at high levels in the liver. Its activation by the drug gemfibrozil reduces clinical events in humans with established atherosclerosis, but the underlying mechanisms are incompletely defined. To clarify the role of PPARα in vascular disease, we crossed PPARα-null mice with apoE-null mice to determine if the genetic absence of PPARα affects vascular disease in a robust atherosclerosis model. On a high-fat diet, concentrations of atherogenic lipoproteins were higher in PPARα-/-apoE-/- than in PPARα+/+apoE-/- mice, due to increased VLDL production. However, en face atherosclerotic lesion areas at the aortic arch, thoracic aorta, and abdominal aorta were less in PPARα-null animals of both sexes after 6 and 10 weeks of high-fat feeding. ---Despite gaining as much or more weight than their PPARα+/+apoE-/- littermates, PPARα-/-apoE-/-mice had lower fasting levels of glucose and insulin. PPARα-null animals had greater suppression of endogenous glucose production in hyperinsulinemic clamp experiments, reflecting less insulin resistance in the absence of PPARα. PPARα-/-apoE-/- mice also had lower blood pressures than their PPARα+/+apoE-/- littermates after high-fat feeding. These results suggest that PPARα may participate in the pathogenesis of diet-induced insulin resistance and atherosclerosis.