The role of microbial triggers in the pathogenesis of the ankylosing spondylitis (AS) has remained an active area of clinical and basic research but remains unresolved. We have recently found evidence of an important role for TLR4 in experimental reactive arthritis, raising the question to be addressed whether genetic polymorphisms in TLR4 affects susceptibility to AS. Innate immune responses to Gram-negative bacteria involve in a central role the binding of lipopolysaccharide to TLR4. Two commonly occurring SNPs in the human TLR4 gene (Asp299Gly and Thr399Ile) have been shown to be associated with increased risk of Gram-negative bacteremia in sepsis patients and with susceptibility to inflammatory bowel disease. It remains unresolved whether these SNPs are associated with AS and we have addressed this in a relatively genetically homogeneous population in Korea. A cohort of 200 Korean AS patients and 197 ethnically matched controls were studied. All patients were native Koreans with AS satisfying the modified New York criteria. Korean controls were examined and confirmed to be unaffected by AS. All subjects were genotyped for two functional SNPs in the TLR4 gene: Asp299Gly (A/G polymorphism) and TLR-4 (Thr399Ile) (C/T polymorphism) The Sequenom MassARRAY system was used for genotyping (Sequenom Inc., San Diego, CA, USA). All cases and controls were homozygous for the (A) allele for 299 variant and similarly for the 399 variant all cases and controls were homozygous for the (C) allele. Genetic-environmental interactions figure prominently in current concepts of the pathogenesis of AS. Our findings indicate that the polymorphisms in the TLR4 gene cannot be regarded as major contributors to AS susceptibility in the Korean population.