Abstract Introduction Interleukin-6 (IL-6) cytokine signaling is key in Rheumatoid Arthritis (RA) pathophysiology. Blocking IL-6 receptor (IL6R) has proven to be a highly effective treatment to prevent joint damage. This study was performed to investigate the association between the genetic variation at IL6R gene and the severity of joint damage in RA. Methods IL6R gene tagging SNPs ( n = 5) were genotyped in a discovery group of 527 RA patients from 5 different university hospitals from Spain. For each marker, a linear regression analysis was performed using an additive model and adjusting for the years of evolution of the disease, autoantibody status, gender and age. Haplotypes combining the SNPs were also estimated and tested for association with the level of joint destruction. Using an independent cohort of 705 RA patients from 6 university hospitals we performed a validation study of the SNPs associated in the discovery phase. Results In the discovery group we found a highly significant association between IL6R SNP rs4845618 and the level of joint destruction in RA ( P = 0.0058, P corrected = 0.026), and a moderate association with SNP rs4453032 ( P = 0.02, P corrected = 0.05). The resulting haplotype from both SNPs was more significantly associated with joint damage ( P = 0.0037, P corrected = 0.011). Using the validation cohort, we replicated the association between the two IL-6R SNPs with the degree of joint destruction in RA ( P = 0.007 and P = 0.04, meta-analysis P = 0.00011 and P = 0.0021, respectively), and the haplotype association ( P = 0.0058, meta-analysis P = 6.64 e-5). Conclusions Genetic variation at IL6R gene is associated with joint damage in RA.