In a prior study, we have shown that TNF- neutralization improves inflammatory markers and total adiponectin in patients with metabolic syndrome, without improving insulin sensitivity. In this study, we sought to extend our understanding of the effects of TNF- neutralization in this human model of obesity, by investigating the responses of high molecular weight (HMW) adiponectin, resistin, leptin, and muscle adiposity, to etanercept in patients with metabolic syndrome. 56 men and women with metabolic syndrome enrolled in a double blind randomized placebo-controlled trial. Circulating concentrations of total and HMW adiponectin, resistin and leptin were determined at baseline and after 4 weeks of treatment with etanercept. Muscle adiposity was measured by computed tomography (CT). Although etanercept increased total adiponectin concentration, the HMW form, which is thought to mediate insulin sensitivity, was unchanged. Thus, the ratio of HMW to total adiponectin decreased following etanercept treatment compared to placebo (-0.03 ± 0.03 vs. 0.06 ± 0.03, P=0.02). Resistin tended to decrease in the etanercept-treated group compared to placebo (-0.6 ± 0.7 vs. 1.2 ± 0.7 ng/mL, P=0.06), whereas leptin was not altered. Etanercept decreased muscle attenuation on CT (-0.61 ± 0.64 HU vs. 1.54 ± 0.77 HU in placebo, P=0.04), suggesting an increase in muscle adiposity. Together, these results demonstrate that neutralization of TNF- in obese humans results in differential effects on critical adipokines and body composition indices. These findings may help explain the lack of effect on insulin sensitivity and extend our knowledge of the biological effects of TNF- neutralization in obesity.