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-&bgr;1, -&bgr;2, and -&bgr;3 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-&bgr; in the development and composition of advanced atherosclerotic lesions. In the present study, we show that inhibition of TGF-&bgr; signaling using a neutralizing anti–TGF-&bgr;1, -&bgr;2, and -&bgr;3 antibody accelerates the development of atherosclerotic lesions in apoE-deficient mice. Moreover, inhibition of TGF-&bgr; signaling favors the development of lesions with increased inflammatory component and decreased collagen content. These results identify a major protective role for TGF-&bgr; in atherosclerosis.