<p>Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially haplotypes(hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, , localizes to risk, neutral, and protective haplotypes. and , nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. , shows no primary MS association. Two Canadian cohorts ( = 830 and = 438 trios) genotyped for , and alleles were tested for association using TDT. To evaluate epistasis involving , transmissions from -negative parents were stratified by the presence/absence of in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. increased disease risk when combined with , thereby unambiguously implicating in MS susceptibility. Three-locus haplotypes demonstrated that and each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with . Incomplete haplotypes bearing only or did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.</p>