The possible contribution of tumor necrosis factor-α (TNF-α) to the development of obesity-associated insulin resistance in humans is still controversial. Our study investigated the effect of TNF-α neutralization on insulin resistance in healthy, obese and insulin resistant men. We performed a prospective, randomized, double-blind placebo-controlled trial in nine young, healthy obese male subjects with metabolic syndrome and insulin resistance. Volunteers received three infusions (wks 0, 2 and 6) of infliximab or placebo. Insulin resistance was measured at baseline and after 70 d by homeostatic model assessment (HOMA) index as well as by minimal model analysis of an intravenous glucose tolerance test. Endothelial function was accessed before and after intervention by flow mediated dilation. Infliximab improved the inflammatory status as indicated by reduced high sensitivity C-reactive protein (hsCRP) and fibrinogen levels (2.77 ± 0.6 to 1.8 ± 0.5 µg/L, and 3.42 ± 0.18 to 3.18 ± 0.28 g/L; (day 0 and day 70, P = 0.020 and 0.037 respectively), but did not improve insulin resistance (HOMA index and intravenous glucose-tolerance test [ivGGT]) or endothelial function. Despite improvements in inflammatory status, chronic TNF-α neutralization does not improve insulin resistance or endothelial function in seemingly healthy, but obese, insulin-resistant volunteers. This study severely questions the proposal that TNF-α is a causative link between adiposity and insulin resistance.