Objective.Studying statistical gene-gene interactions (epistasis) has been limited by the difficulties in performance, both statistically and computationally, in large enough sample numbers to gain sufficient power. Three large Immunochip datasets from cohort samples recruited in the United Kingdom, United States, and Sweden with European ancestry were used to examine epistasis in rheumatoid arthritis (RA).Methods.A full pairwise search was conducted in the UK cohort using a high-throughput tool and the resultant significant epistatic signals were tested for replication in the United States and Swedish cohorts. A forward selection approach was applied to remove redundant signals, while conditioning on the preidentified additive effects.Results.We detected abundant genome-wide significant (p < 1.0e-13) epistatic signals, all within the MHC region. These signals were reduced substantially, but a proportion remained significant (p < 1.0e-03) in conditional tests. We identified 11 independent epistatic interactions across the entire MHC, each explaining on average 0.12% of the phenotypic variance, nearly all replicated in both replication cohorts. We also identified non-MHC epistatic interactions between RA susceptible loci LOC100506023 and IRF5 with Immunochip-wide significance (p < 1.1e-08) and between 2 neighboring single-nucleotide polymorphism near PTPN22 that were in low linkage disequilibrium with independent interaction (p < 1.0e-05). Both non-MHC epistatic interactions were statistically replicated with a similar interaction pattern in the US cohort only.Conclusion.There are multiple but relatively weak interactions independent of the additive effects in RA and a larger sample number is required to confidently assign additional non-MHC epistasis.