Aims: Despite vast clinical experience linking diabetes and atherosclerosis, the molecular mechanisms leading to accelerated vascular damage are still unclear. Here we investigated the effects of Nuclear Factor of Activated T-cells (NFAT) inhibition on plaque burden in a novel mouse model of type 2 diabetes that better replicates human disease. Methods & Results: IGF-II/LDLR-/-ApoB100/100 mice were generated by crossbreeding LDL receptor deficient mice that synthesize only apolipoprotein B100 (LDLR-/-ApoB100/100) with transgenic mice over-expressing insulin-like growth factor-II (IGF-II) in pancreatic β cells. Mice have mild hyperglycemia and hyperinsulinemia, and develop complex atherosclerotic lesions. In vivo treatment with the NFAT blocker A-285222 for 4 weeks reduced atherosclerotic plaque area and degree of stenosis in the brachiocephalic artery of IGFII/ LDLR-/-ApoB100/100 mice, as assessed non-invasively using ultrasound biomicroscopy prior and after treatment, and histologically after termination. Treatment had no impact on plaque composition (i.e. muscle, collagen, macrophages). The reduced plaque area could not be explained by effects of A-285222 on plasma glucose, insulin or lipids. Inhibition of NFAT was associated with increased expression of atheroprotective NOX4 and of the anti-oxidant enzyme catalase in aortic vascular smooth muscle cells (VSMCs). Conclusions: Targeting the NFAT signaling pathway may be an attractive approach for the treatment of diabetic macrovascular complications.