The aim of this study was to investigate the complex association pattern of the extended major histocompatibility complex (xMHC) region with rheumatoid arthritis (RA) susceptibility to identify effects independent of HLA-DRB1. A total of 1804 RA cases and 1474 controls were included. High-resolution HLA-DRB1 typing was performed. Subjects were genotyped for 1546 single-nucleotide polymorphisms (SNPs) using Affymetrix GeneChip 500 K (Santa Clara, CA, USA) as part of the Wellcome Trust Case Control Consortium Study. Statistical analysis was carried out using PLINK. To avoid confounding by RA-associated HLA-DRB1 alleles, we analyzed xMHC SNPs using a data set with pairwise matching of cases and controls on DRB1 genotypes. A total of 594 case-control pairs with identical DRB1 genotypes were identified. After this adjustment, 104 SNPs remained significantly associated with RA (P<0.05), suggesting that additional RA loci independent of HLA-DRB1 can be found in the xMHC region. Of these, four loci showed the strongest associations with RA (P<0.005): ZNF391, the olfactory receptor (OR) gene cluster, C6orf26-RDBP and HLA-DPB1-COL11A2. An additional locus mapping to the BTN (butyrophilin) cluster showed independent association with RA in anti-cyclic citrullinated peptide-positive patients exclusively. We have validated the previously described independent association of the HLA-DPB1-COL11A2 locus with RA. In addition, association with three novel independent RA loci in the xMHC region (ZNF391, OR2H1 and C6orf26-RDBP) has been detected.