Objective Recently, a functional PTPN22 variant (R263Q; rs33996649) was found to be associated with systemic lupus erythematosus (SLE). This study was undertaken to analyze the influence of this polymorphism on the risk of rheumatoid arthritis (RA). Methods RA patients (n = 5,579) were recruited from outpatient clinics from 6 different countries (Spain, New Zealand, the UK, Norway, The Netherlands, and Germany). Healthy controls (n = 5,392) were recruited from the same areas. There was 100% power to detect an effect equivalent to that observed in SLE. Samples were genotyped for the PTPN22 R263Q (rs33996649) and PTPN22 R620W (rs2476601) polymorphisms using a TaqMan 5′-allele discrimination assay. The effect of the R263Q variant was analyzed in isolation and in combination with the effect of R620W, using Unphased and Stata 10 software. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined. Results The minor allele A of PTPN22 R263Q was significantly associated with a lower risk of RA in the pooled analysis of the 6 populations (P = 0.016, Mantel-Haenszel pooled OR 0.80 [95% CI 0.67-0.96]), independent of the effect of the R620W polymorphism. Both polymorphisms had an additive effect. The more RA risk alleles carried (R263Q G allele, R620W T allele), the higher the RA risk (for 2 versus 1 risk allele P = 0.014, OR 1.28 [95% CI 1.05-1.55], for 3 versus 1 risk allele P = 6.67 × 10 -11, OR 2.01 [1.63-2.48], and for 4 versus 1 risk allele P = 6.50 × 10-11, OR 3.55 [2.42-5.20]). Conclusion Our findings indicate that the minor allele of the PTPN22 R263Q polymorphism is associated with a lower risk of RA. This association is independent of the well-established association between PTPN22 R620W and RA. Both polymorphisms have an additive effect on the risk of RA. © 2011 by the American College of Rheumatology.