In a prior study, we have shown that tumor necrosis factor (TNF)-α neutralization improves inflammatory markers and total adiponectin in patients with the metabolic syndrome, without improving insulin sensitivity. In this study, we sought to extend our understanding of the effects of TNF-α 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 the metabolic syndrome. Fifty-six men and women with the 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 wk 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 with placebo (−0.03 ± 0.03 vs. 0.06 ± 0.03, P = 0.02). Resistin tended to decrease in the etanercept-treated group compared with 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 Hounsfield units (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-α in obese humans results in differential effects on critical adipokines and body composition indexes. These findings may help to explain the lack of effect on insulin sensitivity and extend our knowledge of the biological effects of TNF-α neutralization in obesity.