<h3>Objectives</h3> The Xq28 region containing <i>IRAK1</i> and <i>MECP2</i> has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between <i>IRAK1</i> and <i>MECP2</i>, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE. <h3>Methods</h3> We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing <i>IRAK1, MECP2</i> and seven adjacent genes (<i>L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1</i> and <i>TMEM187</i>), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups. <h3>Results</h3> Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p&lt;5×10⁻⁸ with consistent association in subjects with African ancestry. Of these, six SNPs located in the <i>TMEM187-IRAK1-MECP2</i> region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p_meta= 1.3×10⁻²⁷, OR=1.43), and thus was considered to be the most likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of <i>MECP2</i>, but not <i>IRAK1</i>, in SLE patients (p=0.0012) and healthy controls (p=0.0064). <h3>Conclusions</h3> These data suggest contributions of both <i>IRAK1</i> and <i>MECP2</i> to SLE susceptibility.