AIMS: Progressive deposition of cholesterol in the arterial wall characterizes atherosclerosis, which underpins most cases of myocardial infarction and stroke. Insulin-like growth factor-1 (IGF-1) is a hormone that regulates systemic growth and metabolism and possesses anti-atherosclerotic properties. We asked whether endothelial-restricted augmentation of IGF-1 signalling is sufficient to suppress atherogenesis. METHODS AND RESULTS: We generated mice with endothelial-restricted over-expression of human wild-type (WT) IGF-1R (hIGFREO/ApoE-/-) or a signalling-defective K1003R mutant human IGF-1R (mIGFREO/ApoE-/-) and compared them with their respective ApoE-/- littermates. hIGFREO/ApoE-/- had less atherosclerosis, circulating leucocytes, arterial cholesterol uptake, and vascular leakage in multiple organs, whereas mIGFREO/ApoE-/- did not exhibit these phenomena. Over-expressing WT IGF-1R in human umbilical vein endothelial cells (HUVECs) altered the localization of tight junction proteins and reduced paracellular leakage across their monolayers, whilst over-expression of K1003R IGF-1R did not have these effects. Moreover, only over-expression of WT IGF-1R reduced HUVEC internalization of cholesterol-rich low-density lipoprotein particles and increased their association of these particles with clathrin, but not caveolin-1, implicating it in vesicular uptake of lipoproteins. Endothelial over-expression of WT vs. K1003R IGF-1R also reduced expression of YAP/TAZ target genes and nuclear localization of TAZ, which may be relevant to its impact on vascular barrier and atherogenesis. CONCLUSION: Endothelial IGF-1 signalling modulates both para- and transcellular vascular barrier function. Beyond reducing atherosclerosis, this could have relevance to many diseases associated with abnormal vascular permeability.