Macrophages are phagocytic cells that play essential roles in innate immunity and lipid homeostasis. The uptake of modified lipoproteins is an important early event in the development of atherosclerosis. We analyzed the ability of modified LDL (oxidized and acetylated) to alter the expression and activity of arginases (ArgI and ArgII) in macrophages. We show that ArgI expression is potently induced by both oxLDL and acLDL in macrophages. We further show that this effect is mediated by peroxisome proliferator-activated receptors (PPARs). Arginase I expression is highly responsive to agonists for PPAR and PPAR but not PPAR. Moreover, the induction of ArgI by both PPAR agonists and IL-4 is blocked in macrophages from PPAR- and -deficient mice. Functionally, PPAR activity induces macrophage activation towards a more Th2 immune phenotype in a model of Leishmania major infection. We show that PPAR and ligands promote intracellular amastigote growth in infected macrophages, and this effect is dependent on both PPAR expression and arginase activity. Collectively, our results strongly suggest that arginase I is a key marker of the alternative program triggered by PPARs in macrophages.