The aim of this study was to characterize alterations in vascular structure and mechanics in murine mesenteric arteries from obese non-hypertensive mice, as well as their relationship with adipokines. Four-week old C57BL/6J male mice were assigned either to a control (C, 10% kcal from fat) or a high-fat diet (HFD, 45% kcal from fat) for 32 weeks. HFD animals weighed 30% more than controls (p b 0.001), exhibited similar blood pressure, increased leptin, insulin and superoxide anion (O2 •−) levels, and reduced adiponectin levels and nitric oxide (NO) bioavailability. Arterial structure showed an outward remodeling with an increase in total number of both adventitial and smoothmuscle cells inHFD.Moreover, HFDmice exhibited an increased arterial stiffness assessed by β-values (C=2.4±0.5 vs HFD=5.3±0.8; p b 0.05) and aortic pulse wave velocity (PWV, C=3.4±0.1 vs HFD = 3.9 ± 0.1; p b 0.05). β-Values and PWV positively correlated with leptin, insulin or O2 •− levels, whereas they negatively correlated with adiponectin levels and NO bioavailability (p b 0.01). A reduction in fenestrae number together with an increase in type-I collagen amount (p b 0.05) were observed in HFD. These data demonstrate that HFD accounts for the development of vascular remodeling and arterial stiffness associated with adipokine dysregulation and oxidative stress, independently of hypertension development.