Objective To investigate whether a human X chromosome locus of IRAK1 and MECP2 is associated with susceptibility to rheumatoid arthritis (RA), an autoimmune disease that predominantly affects women. Methods A total of 2,334 unrelated Korean participants (including 1,318 patients with RA) were genotyped for 5 tag single-nucleotide polymorphisms (SNPs) and 3 additional SNPs in an Xq28 region harboring MECP2 and IRAK1. Twenty-nine additional neighboring SNPs were imputed using the Korean HapMap Project data. All 37 SNPs were statistically tested for association with RA susceptibility, and 2 SNPs associated with RA were examined for their functional effects. Results RA susceptibility was associated with multiple SNPs in a 79-kb linkage disequilibrium block harboring both MECP2 and IRAK1. The most significant association was for MECP2 SNP rs1734792 (P = 0.00089), but 2 nonsynonymous IRAK1 SNPs, rs1059702 (P = 0.0034) and rs1059703 (P = 0.0042), which were in strong linkage disequilibrium with the MECP2 SNP (D = 0.87 and 0.91, respectively) affected IRAK1 protein activity. The major haplotype of the 2 nonsynonymous SNPs was associated with a 1.7-fold increase in RA susceptibility versus the minor haplotype (P = 0.0082), and with increased IRAK1 activity, which was demonstrated by a 1.7-fold increase in the intracellular activity of transcription factor NF-B. Conclusion Our findings indicate that RA susceptibility is associated with multiple SNPs in MECP2 and IRAK1, but high linkage disequilibrium between them does not allow for further localization. Therefore, both genes remain candidates. Nevertheless, the major haplotype of the 2 nonsynonymous IRAK1 SNPs encoding for pPhe196Ser and pSer532Leu confers enhanced IRAK1 activity and, consequently, enhanced susceptibility to RA, as compared to the minor haplotype.