Single-nucleotide polymorphisms (SNPs) in the UHRF gene have been shown to be associated with systemic lupus erythematosus (SLE) in European and Hong Kong Chinese, but statistically significant evidence for association has not been found in a mainland Han Chinese population. Therefore, we selected SNP rs13205210 located in UHRF1BP1 as a candidate association from our previously published genome-wide association study (GWAS) data of SLE (1,047 cases and 1,205 controls from a mainland Han Chinese population) to explore the association between the UHRF1BP1 gene and SLE. We conducted a large-scale replication study in an additional independent sample of 3,509 cases and 8,246 controls from a mainland Han Chinese population. Real-time PCR was used to determine gene expression differences in peripheral blood mononuclear cells (PBMCs) from cases and controls. As a result, we replicated the association between the UHRF1BP1 gene and SLE (rs13205210, missense, P-meta( )= 2.26E-17, odds ratio = 1.41) by a meta-analysis of our previous GWAS and this replication study involving a total of 4,556 cases and 9,451 controls. The UHRF1BP1 mRNA expression level in PBMCs was significantly decreased in patients with SLE compared with that in healthy controls. SNP rs13205210 exhibited an expression quantitative trait loci effect on the UHRF1BP1 gene in PBMCs from patients. In conclusion, this study not only suggests that the UHRF1BP1 gene was associated with SLE in a mainland Han Chinese population, but also implied that it might be a common genetic factor contributing to SLE susceptibility in multiple populations.