Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting ~ 1% of the population worldwide. The genome wide association studies on RA patients revealed linkage with 1p36 locus containing peptidyl arginine deiminase 4 (PADI4) genes. Case-control association studies and mRNA stability assays reported the association of PADI4 gene with RA in Korean and Japanese populations. However, such association was not found in Spanish population. Differences in the association of PADI4 with RA in different populations prompted the present study in Indian population. Anti-CCP antibodies, RF antibody, disease activity scores at 28 joints (DAS28) and mutations in three exons of PADI4 were investigated in RA patients and control group. Among the patients anti-CCP antibody levels were found to be associated with high DAS28 values (r = 0.4526, P < 0.0001). Polymorphism in exon-4 (padi4_104, [rs1748033]) of PADI4 showed significant association of ‘C’ allele with RA in the study population (P = 0.0008). Polymorphism in exon-3 (padi4_92, [rs874881]) also exhibited moderate association with the disease (P = 0.075). However, no association of the disease was found with the SNPs padi4_89 [rs11203366] and padi4_90 [rs11203367] in exon-2 of PADI4.