Toll-like receptor-4 (TLR4), an important mediator of the innate immune response, is expressed in atherosclerotic lesions. The common single nucleotide exchange (Asp299Gly) of the TLR4 gene has been previously reported to impair TLR4 function and to be associated with a decreased risk of carotid atherosclerosis. Therefore, we aimed to detect the potential impact of TLR4 genotypes on the risk of cerebral ischemia. We studied the prevalence of two common polymorphisms of the TLR4 gene (Asp299Gly and Thr399Ile) in 3 independent study populations: (1.) in a cross-sectional study including 769 patients either with type 1 or type 2 diabetes mellitus, of whom 56 (7.2%) had a history of cerebral ischemia (study 1), (2.) a case-control study (study 2) including 128 consecutive patients with cerebral ischemia, mean age 60 +/- 10.9 years and 139 control subjects, and (3.) a case-control study (study 3) including 171 young adults aged < 50 years with cerebral ischemia and 204 control individuals. In all subjects, Asp299Gly and Thr399Ile were detected by restriction length analysis. The prevalence of the TLR4 genotypes was essentially the same between patients with cerebral ischemia and control subjects in all 3 study populations. Furthermore, there was also no association with the subgroup of atherosclerotic stroke in both case-control studies populations. Although TLR4 polymorphisms are associated with a decreased risk of carotid atherosclerotic lesions, our findings indicate that they do not influence the prevalence of cerebral ischemia. This implies that the Asp299Gly TLR4-allele might have a protective role in carotid atherosclerosis, but not in cerebral ischemia.