Tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) is a negative regulator of NF-κB activity. We previously reported that the paired tandem polymorphic dinucleotides TT > A (rs148314165, rs200820567 of TNFAIP3) conferred the risk for systemic lupus erythematosus (SLE) in European and Korean populations. We investigated the genetic association of the TT > A variants, as well as the functional coding variant rs2230926 in exon 3 of TNFAIP3 in 1229 Chinese Han SLE patients and 1608 matched population controls. We further evaluated the role of these variants in regulating expression of the TNFAIP3 gene and NF-κB signaling pathway in their peripheral blood mononuclear cells from Chinese SLE patients. The TT > A variants and the TNFAIP3 exon 3 coding variant rs2230926 demonstrated significant associations in SLE (PTT > A = 8.96 × 10−12, odds ratio [OR] = 2.07, 95% confidence interval [CI] = 1.68–2.55). SLE patients carrying the risk A allele showed reduced messenger RNA expression of the TNFAIP3 gene and increased expression of NF-κB1 in PBMCs. Conditional analyses revealed that the TT > A variants are likely to be causal variants in Chinese Han SLE patients. The TT > A variants associated with Chinese Han SLE and negatively regulate the expression of the TNFAIP3 gene resulting in enhanced NF-κB activity.