Systemic sclerosis (SSc) is a complex disease involving multiple genetic factors. An association of the IRF5 polymorphism with SSc was reported in Caucasian populations of Europe and North America, as well as in Japanese populations. The present study aimed to examine whether the SSc-associated SNP rs2004640 of IRF5 gene confer susceptibility to SSc and clinical features of SSc in a Han Chinese population. A Han Chinese cohort consisting of 424 SSc patients and 502 healthy controls were examined in the study. TaqMan assays were carried out to examine the SNP. Exact p-values were obtained (Fishers test) from 2x2 tables of allele counts and disease status. SSc patients of Han Chinese showed increased homozygous TT genotype of the rs2004640 (p = 0.027, odds ratio (OR) = 1.4, CI =1.03-1.93), which was significantly associated with pulmonary fibrosis of SSc and ATA-positive SSc of Han Chinese. The lcSSc and ACA-positive SSc of Han Chinese appeared also in association with the increased T allele frequency. However, the Chinese dcSSc did not show any association with the rs2004640. The results were consistent with previous reports in other ethnic populations in supporting the notion that polymorphisms of IRF5 may play an important role in susceptibility to SSc.