Atherosclerosis is a disease of the arterial wall that seems to be tightly modulated by the local inflammatory balance. Whereas a large body of evidence supports a role for proinflammatory mediators in disease progression, the understanding of the role of the antiinflammatory component in the modulation of plaque progression is only at its beginning. TGF-β1, -β2, and -β3 are cytokines/growth factors with broad activities on cells and tissues in the cardiovascular system and have been proposed to play a role in the pathogenesis of atherosclerosis. However, no study has examined the direct role of TGF-β in the development and composition of advanced atherosclerotic lesions. In the present study, we show that inhibition of TGF-β signaling using a neutralizing anti–TGF-β1, -β2, and -β3 antibody accelerates the development of atherosclerotic lesions in apoE-deficient mice. Moreover, inhibition of TGF-β signaling favors the development of lesions with increased inflammatory component and decreased collagen content. These results identify a major protective role for TGF-β in atherosclerosis.