Rheumatoid arthritis (RA) is a systemic inflammatory disease that causes chronic inflammation of the joints. Analysis of genetic variants offers promise for guiding treatment and improving outcomes in RA. High-mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein found in all mammal eukaryotic cells that participates in several biological functions including immune response, cell survival and apoptosis. We investigated the effects of HMGB1 gene polymorphisms on the risk of RA disease progression in a cohort of Chinese Han individuals. Four single nucleotide polymorphisms (SNPs) from the HMGB1 gene were selected and genotyped in 232 patients with RA and 353 healthy controls. We found that having one C allele in rs1360485 and one G allele in rs2249825 polymorphisms lowered the risk of RA in females. Moreover, among healthy controls, those who bore the C/G/T haplotype at SNPs rs1360485, rs2249825 and rs1412125 were at reduced risk of developing RA by 0.13-fold (p <0.05). This is the first report to examine the risk factors associated with HMGB1 SNPs in the development of RA disease in the Chinese Han population.