OBJECTIVE: Obesity is associated with chronic inflammation due to overproduction of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha. We assessed the effects of TNF-alpha neutralization by infliximab on vascular reactivity during hyperinsulinemia in obesity-related metabolic syndrome. RESEARCH DESIGN AND METHODS: Vascular responses to intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in patients with metabolic syndrome, before and after administration of infliximab. RESULTS: Patients had blunted vasodilator responses to ACh and SNP during hyperinsulinemia compared with control subjects; a potentiation of the responsiveness to both ACh and SNP, however, was observed in patients following infliximab. The antioxidant vitamin C improved the vasodilator response to ACh in patients with metabolic syndrome, but its effect was not further enhanced by concurrent administration of infliximab. CONCLUSIONS: TNF-alpha neutralization ameliorates vascular reactivity in metabolic syndrome during hyperinsulinemia, likely in relation to decreased oxidative stress, thereby suggesting an involvement of inflammatory cytokines in vascular dysfunction of these patients.