Objective The present study was undertaken to investigate the association of peptidyl-arginine-deiminase type IV gene (PADI4) single nucleotide polymorphisms (SNPs) with rheumatoid arthritis (RA) susceptibility, and to determine whether there is any impact of PADI4 polymorphisms on RA subsets or phenotypes in a large Chinese Han cohort. Methods Two PADI4 SNPs (rs2240340 and rs1748033) were genotyped in 1216 Chinese Han RA patients and 1040 unaffected controls by TaqMan SNP Assays. Serum anti-CCP antibody and anti-PAD4 antibody levels were measured by ELISA. Bone destruction was scored by Sharp-van der Heijde scores (SHSs) of hands in 463 patients. Results The two SNPs rs2240340 and rs1748033 of PADI4 showed strong association with RA susceptibility (OR=1.23, 95% CI 1.09-1.38, p=6.66x10(-4); and OR=1.24, 95% CI 1.10-1.41, p=6.98x10(-4), respectively). RA risk genotypes of PADI4 were specifically associated with anti-CCP positive RA (rs2240340: 19=5.13x10(-6); rs1748033: p=2.97x10(-3), respectively). Furthermore, there was a trend association between PADI4 rs2240340 and radiographic severity, though it did not reach statistical significance (p=0.088). Conclusion Our data provide strong evidence that PADI4 polymorphisms are risk factors contributed to RA susceptibility, especially for anti-CCP positive RA, and may confer higher risk of RA radiographic severity in Chinese Han population.