Since chronic L-arginine supplementation improves insulin sensitivity and endothelial function in nonobese type 2 diabetic patients, the aim of this study was to evaluate the effects of a long-term oral L-arginine therapy on adipose fat mass (FM) and muscle free fat mass (FFM) distribution, daily glucose levels, insulin sensitivity, endothelial function, oxidative stress, and adipokines release in obese type 2 diabetic patients with insulin resistance, submitted to a combined period of hypocaloric diet and exercise training. Thirty-three type 2 diabetic patients were submitted to a hypocaloric diet plus an exercise training program for 21 days. Furthermore, they were divided into two groups in randomised order: the firs group was also treated with L-arginine (8.3 gr a day), the second group with Placebo. Although in Placebo group body weight, waist circumference, daily glucose profiles, fructosamine, insulin, and homeostasis model assessment (HOMA) index significantly decreased, L-arginine supplementation further decreased FM (p<0.05) and waist circumference (p<0.0001) preserving FFM (p<0.03) and improved mean daily glucose profiles (p<0.0001) and fructosamine (p<0.03). Moreover, incremental area of c-GMP (second messenger of nitric oxide; p<0.001), superoxide dismutase (index of anti-oxidant capacity, p<0.01) and adiponectin levels (p<0.02) increased while basal endothelin-1 levels (p<0.01) and leptin/adiponectin ratio (p<0.05) decreased in L-arginine group. Long-term oral L-arginine treatment demonstrated an additive effect compared with a diet and exercise training program alone on glucose metabolism and insulin sensitivity. Furthermore, it improved endothelial function, oxidative stress and adipokines release in obese type 2 diabetic patients with insulin resistance.