Obesity is tightly associated with insulin resistance and endothelial dysfunction. It is suggested that hepatic IR is sufficient to promote progression to cardiovascular disease. We showed recently that specific deletion of liver PTP1B (L-PTP1B), a negative regulator of insulin receptor, improves whole body glucose and lipid homeostasis. Thus, we propose to investigate the impact of these improvements in L-PTP1B-/-mice, on cardiovascular function in the context of diet-induced obesity. Glucose tolerance test was performed on overnight fasted mice by measuring blood glucose values in tail vein bleeds using a LifeScan glucometer immediately before and at 15, 30, 60, and 120 minutes after intraperitoneal injection of glucose. Blood pressure was measured in vivo on conscious mice using a non-invasive tail cuff blood pressure monitoring system (Penlab). Cardiac function was assessed by echocardiography on anesthetized mice (Vevo 2000, Visual Sonics). Vascular function, in L-PTP1B−/− and control mice, fed a chow or high fat diet (HFD) was assessed by myopgraphy technique (DMT). Compared to control littermates, L-PTP1B-/- mice had improved glucose and lipid homeostasis without changes in body mass. HFD feeding increased systolic blood pressure in both mouse groups; however, it was lower in L-PTP1B-/- mice. Structure and function analysis of the left ventricle showed that HFD-feeding decreased cardiac index in control mice, while L-PTP1B−/− mice were fully protected. HFD feeding significantly impaired endothelium-dependent relaxation in response to acetylcholine in aortas taken from control mice compared to chow diet-fed mice, while L-PTP1B−/− mice were protected. Altogether, these data indicate that targeting L-PTP1B may be useful to reduce obesity-associated cardiovascular risk in addition to diabetes.