OBJECTIVE To determine the association of single-nucleotide polymorphisms (SNP) in the cyclooxygenase-2 (COX-2) gene with the risk and radiologic severity of rheumatoid arthritis (RA) in Koreans. METHODS Sequencing of the COX-2 gene using a DNA analyzer revealed genetic variants in 24 Korean DNA samples. A total of 1201 Korean patients with RA and 973 controls were genotyped using the TaqMan method. HLA-DRB1 was genotyped by polymerase chain reaction and sequence-specific oligonucleotide probe hybridization techniques. Logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (95% CI) and the corresponding probability values for each SNP site and haplotype. RESULTS Direct sequencing identified 23 SNP of COX-2 gene, from which 2 common SNP (-1329A-->G and 6365T-->C) were selected based on the linkage disequilibrium status among SNP and minor allele frequencies. The -899G-->C SNP was also studied because it is reportedly associated with the risk of RA. The -1329A-->G SNP was not significantly associated with the risk of RA. However, the risk of RA was significantly lower in the presence of the C allele for 6365T-->C (OR 0.50, 95% CI 0.29-0.85, in a recessive model, and OR 0.80, 95% CI 0.67-0.97, in a codominant model). The C allele for -899G-->C was also associated with a significantly lower risk of RA (OR 0.67, 95% CI 0.48-0.95, in a codominant model). The radiologic severity of RA was not associated with COX-2 polymorphisms. CONCLUSION Our study revealed a possible protective influence of the C allele for 6365T-->C and for -899G-->C in RA.