Objective: Interleukin-18 (IL-18) has been recently demonstrated to improve experimental hyperphagia and insulin resistance. Paradoxically, concentrations of circulating IL-18 in obese subjects and in patients with type 2 diabetes are increased. The objective of this study is to provide an explanation for this paradox. Design: We have hypothesized that cells from obese individuals or from patients with type 2 diabetes mellitus have a diminished response to stimulation with IL-18. IL-18 responsiveness was tested by stimulating blood monocytes of obese or diabetes patients with rIL-18 or microbial components. Results: Obese individuals and patients with type 2 diabetes mellitus exhibit increased circulating concentrations of IL-18. More importantly, leukocytes isolated from obese or type 2 diabetes patients respond poorly after stimulation with IL-18, as reflected by defective interferon-g (IFNg) production. The defective response to IL-18 stimulation was accompanied by a 50% reduction in the expression of IL-18R a and b chains. In addition, cells of patients with obesity and diabetes displayed an impaired release of IFNg after challenge with bacterial or fungal pathogens, which was due to defective IL-18-mediated signaling. Conclusion: Patients with obesity or type 2 diabetes mellitus are characterized by lower responses after stimulation with IL-18. This IL-18 resistance explains the association of obesity and diabetes with high IL-18 circulating concentrations, similar to hyperinsulinemia and hyperleptinemia. IL-18 resistance may represent an important mechanism of the increased susceptibility of these patients to a number of infections.