Fatty acid metabolism is perturbed in atherosclerotic lesions, but whether it affects lesion formation is unknown. To determine whether fatty acid synthesis affects atherosclerosis, we inactivated fatty-acid synthase (FAS) in macrophages of apoE-deficient mice. Serum lipids, body weight, and glucose metabolism were the same in FAS knock-out in macrophages (FASKOM) and control mice, but blood pressure was lower in FASKOM animals. Atherosclerotic extent was decreased 20-40% in different aortic regions of FASKOM as compared with control mice on Western diets. Foam cell formation was diminished in FASKOM as compared with wild type macrophages due to increased apoAI-specific cholesterol efflux and decreased uptake of oxidized low density lipoprotein. Expression of the anti-atherogenic nuclear receptor liver X receptor α (LXRα; Nr1h3) and its downstream targets, including Abca1, were increased in FASKOM macrophages, whereas expression of the potentially pro-atherogenic type B scavenger receptor CD36 was decreased. Peroxisome proliferator-activated receptor α (PPARα) target gene expression was decreased in FASKOM macrophages. PPARα agonist treatment of FASKOM and wild type macrophages normalized PPARα target gene expression as well as Nr1h3 (LXRα). Atherosclerotic lesions were more extensive when apoE null mice were transplanted with LXRα-deficient/FAS-deficient bone marrow as compared with LXRα-replete/FAS-deficient marrow, consistent with antiatherogenic effects of LXRα in the context of FAS deficiency. These results show that macrophage FAS deficiency decreases atherosclerosis through induction of LXRα and suggest that FAS, which is induced by LXRα, may generate regulatory lipids that cause feedback inhibition of LXRα in macrophages.