Abstract Atherosclerotic lesions are asymmetric focal thickenings of the intima of arteries that consist of lipids, various cell types and extracellular matrix (ECM). These lesions lead to vascular occlusion representing the most common cause of death in the Western world. The main cause of vascular occlusion is rupture of atheromatous lesions followed by thrombus formation. Fibronectin (FN) is one of the earliest ECM proteins deposited at atherosclerosis‐prone sites and was suggested to promote atherosclerotic lesion formation. Here, we report that atherosclerosis‐prone apolipoprotein E‐null mice lacking hepatocyte‐derived plasma FN (pFN) fed with a pro‐atherogenic diet display dramatically reduced FN depositions at atherosclerosis‐prone areas, which results in significantly smaller and fewer atherosclerotic plaques. However, the atherosclerotic lesions from pFN‐deficient mice lacked vascular smooth muscle cells and failed to develop a fibrous cap. Thus, our results demonstrate that while FN worsens the course of atherosclerosis by increasing the atherogenic plaque area, it promotes the formation of the protective fibrous cap, which in humans prevents plaques rupture and vascular occlusion. See accompanying article http://dx.doi.org/10.1002/emmm.201200238