Context: Impaired insulin clearance contributes to the hyperinsulinemia of obesity, yet relatively little is known concerning the pathophysiological determinants of insulin clearance in obese populations. Objective: To examine the cross-sectional relationship between insulin clearance and resting sympathetic nervous system activity in a cohort of obese subjects with metabolic syndrome. Participants and Methods: Unmedicated, nonsmoking subjects (31 male, 27 female; aged 56 ± 1 year; body mass index 33.7 ± 0.6 kg/m2) underwent euglycemic hyperinsulinemic clamp to determineinsulin sensitivity (M)andinsulin clearance, assessment of norepinephrine kinetics, peripheral arterial tonometry, Doppler echocardiography, and oral glucose tolerance test. Results: Univariate correlation analyses showed inverse associations between insulin clearance and arterial norepinephrine concentration (r=-0.44, P =.0006), calculated norepinephrine spillover rate (r=-0.33, P =.01), augmentation index (AI, r=-0.37, P =.005), and positive associations with M (r = 0.30, P =.02), Matsuda insulin sensitivity index (r = 0.27, P =.04), and cardiac output (r = 0.27, P =.04). Insulin clearance and sensitivity did not differ between genders, however females had higher AI compared to males (35 ± 3% versus 14 ± 2%, P <.001). In age and gender adjusted stepwise regression analyses, arterial norepinephrine concentration alone explained19% of the variance in insulin clearance. When all significant variables were entered into the regression model, arterial norepinephrine, AI, gender, and M were independent predictors of insulin clearance, together explaining 41% of the variance. Conclusions: Arterial norepinephrine concentration is inverselyandindependently associated with whole-body insulin clearance rate in obese individuals with metabolic syndrome. Prospective studies are needed to determine the direction of causality and the chronology of interactions between insulin clearance and sympathetic neural activity.