Objective— Maternal hypercholesterolemia is associated with a higher incidence and faster progression of atherosclerotic lesions in neonatal offspring. We aimed to determine whether an in utero environment exposing a fetus to maternal hypercholesterolemia and associated risk factors can prime the murine vessel wall to accelerated development of cardiovascular disease in adult life. Methods and Results— To investigate the epigenetic effect in utero, we generated genetically identical heterozygous apolipoprotein E–deficient progeny from mothers with a wild-type or apolipoprotein E–deficient background. A significant increase in loss of endothelial cell volume was observed in the carotid arteries of fetuses of apolipoprotein E–deficient mothers, but fatty streak formation was absent. Spontaneous atherosclerosis development was absent in the aorta and carotid arteries in adult life. We unilaterally placed a constrictive collar around the carotid artery to induce lesion formation. In offspring from apolipoprotein E–deficient mothers, collar placement resulted in severe neointima formation in 9 of 10 mice analyzed compared with only minor lesion volume (2 of 10) in the progeny of wild-type mothers. Conclusions— We conclude that the susceptibility to neointima formation of morphologically normal adult arteries is already imprinted during prenatal development and manifests itself in the presence of additional atherogenic risk factors in adult life. Future research will concentrate on the mechanisms involved in this priming process, as well as on prevention strategies.