Toll-like receptor 4 (TLR4) plays a key role in the activation of innate immune responses. Loss-of-function mutations in TLR4 prevent diet-induced obesity and insulin resistance (IR). We conducted a population cross-sectional study to evaluate whether Asp299Gly (rs4986790) TLR4 gene polymorphism is associated with metabolic syndrome (MS), surrogates of IR, and syndromes of lipid accumulation (SLAs) in Argentinean healthy male subjects. rs4986790 was genotyped in 621 healthy unrelated male blood donors. National Cholesterol Education Program/Adult Treatment Panel III-MS (NCEP/ATP III-MS); SLAs such as enlarged waist elevated triglyceride syndrome (EWET), hypertriglyceridemic waist (HW), and overweight-lipid syndrome (OLS); and surrogates of IR were assessed. The prevalence of MS, OLS, and EWET was significantly higher among Asp299Asp carriers (P or=5. This is the first report to find, in Argentinean healthy male blood donors, associations between the Asp299Asp genotype of rs4986790 TLR4 gene polymorphism and high risk for NCEP/ATP III-MS, SLAs, and surrogates of IR. These findings are consistent with previous functional and observational studies showing that Asp299 allele, in comparison with Gly299, is associated with increased TLR4 activation, higher levels of inflammatory cytokines, acute-phase reactants and soluble adhesion molecules, and higher risk of atherosclerosis.