Background Obesity is associated with insulin resistance, inflammation, metabolic dysfunction, and atherosclerosis. This study investigates the effects of weight loss, intense exercise, and moderate caloric restriction on insulin resistance, lipids, inflammatory biomarkers, carotid artery distensibility index (CaDI), and carotid intima media thickness (CIMT). Methods Seventeen sedentary morbidly obese contestants in the “Biggest Loser” television program completed the 7-month intense-exercise and moderate-restricting calories program; 3 were excluded due to lack of follow-up CIMT. Serum insulin level, glucose, lipid profile, high-sensitivity C-reactive protein (CRP), hemoglobin A1c (HbA1c), resistin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor receptor-II (TNFRII), lipoprotein a (Lp[a]), sex hormone binding globulin (SHBG), blood pressure, body fat, weight, CaDI, and CIMT were measured at baseline and 7-month follow-up. CIMT was measured 5-10 mm below the common carotid bifurcation during mid-diastolic phase. CaDI was defined as: (End-systole – End-diastole common-carotid cross-sectional area)/(End-diastole common-carotid cross-sectional-area × systemic pulse pressure) × 1000. Insulin resistance was calculated by homeostatic model assessment (HOMA) index. Results At 7-month follow-up, major reductions in weight (−39%), body fat (−66%), serum insulin level (−52%), glucose (−21%), high-sensitivity CRP (−81%), HbA1c (−11%), PAI-1 (−49%), TNFRII (−12%), and CIMT (−25%), and increases in CaDI (132%), resistin (344%), adiponectin (94%), Lp(a) (73%), and SHBG (94%) were observed. The improvement in CaDI was positively correlated with increases in adiponectin, Lp(a), SBHG, and resistin ( r 2 = 0.86, P = .009), but inversely with PAI-1, TNFRII, CRP, and IR ( r 2 = −0.64, P = .01). Strong inverse correlation was noted between decreases in CIMT and increases in CaDI ( r 2 = 0.65, P = .001). Conclusion In morbidly obese individuals, intense exercise with moderate caloric restriction over 7 months is associated with a dramatic improvement in carotid vascular function and atherosclerosis risk factors, as well as a reduction in inflammatory biomarkers, lipids, insulin resistance, and CIMT.