Abstract In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of HLA-DRB1 alleles, called shared epitope alleles (SE), is the highest genetic risk factor. Here, we aimed to investigate whether gene-gene interactions influence this HLA-DRB1 related major disease risk; specifically, we set out to test if non-HLA SNPs, conferring low diseases risk on their own, can modulate the HLA-DRB1 SE effect to develop ACPA-positive RA. To address this question, we computed the attributable proportion (AP) due to additive interaction at genome-wide level for two independent ACPA-positive RA cohorts: the Swedish EIRA and the North American NARAC. We found a strong enrichment of significant interactions (AP p-values<0.05) between the HLA-DRB1 SE alleles and a group of SNPs associated with ACPA-positive RA in both cohorts (Kolmogorov-Smirnov [KS] test D=0.35 for EIRA and D=0.25 for NARAC, p<2.2e-16 for both). Interestingly, 201 out of 1,492 SNPs in consistent interaction for both cohorts, were eQTLs in SE alleles context in PBMCs from ACPA-positive RA patients. Finally, we observed that the effect size of HLA-DRB1 SE alleles for disease decreases from 5.2 to 2.5 after discounting the risk alleles of the two top interacting SNPs (rs2476601 and rs10739581, AP FDR corrected p <0.05). Our data demonstrate that the association between the HLA-DRB1 SE alleles and the risk of ACPA-positive RA is modulated by massive genetic interactions with non-HLA genetic variants.