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The human major histocompatibility complex (MHC) class II region is associated with genetic susceptibility to multiple sclerosis (MS). Roles for HLA class I loci have been supported in several case–control studies, but this methodology does not consider the known linkage disequilibrium (LD) between class I and II loci. In 1258 individuals from 294 MS families, we analysed class I and II interactions. Using transmission disequilibrium test and haplotype analyses, we found positive associations between MS and severalHLA-DRB1*15-HLA-Ahaplotypes includingHLA-DRB1*15-HLA-A*02(P= 2.41 × 10−5) and-HLA-A*03(P= 8.42 × 10−6) and severalHLA-DRB1*15-HLA-Bhaplotypes includingHLA-DRB1*15-HLA-B*07(P= 2.23 × 10−10).HLA-DRB1*15haplotypes divergent for reportedHLA-Aallelic associations were equally over-transmitted, illustrating no detectable effect ofHLA-Aor-Balleles incison susceptibility.HLA-Aand-Balleles on haplotypes not bearingHLA-DRB1*15were not over-transmitted. Similarly, general over-transmission ofHLA-DRB1*15haplotypes was independent of theHLA-Ballele present. Furthermore,HLA-B*07haplotypes fromHLA-DRB1*X-HLA-B*X/HLA-DRB1*X-HLA-B*07heterozygous parents were transmitted per random expectation giving no indication ofHLA-Bindependence ortranscomplementation ofHLA-DRB1*15byHLA-DRB1*X-HLA-B*07haplotypes. These results imply that many reports of class I allelic associations in MS are class II dependent, secondary to LD with class II loci. The lack of independent class I associations suggests that virus-related class I-antigen complexes are not T-cell targets in MS. The inability to replicate confirmed case–control associations highlights the importance of family-based analyses. The frequency of allelic associations not being replicated emphasizes the requirement for constructing multi-locus haplotypes in dissecting associations in regions of tight LD.

Transmission of class I/II multi-locus MHC haplotypes and multiple sclerosis susceptibility: accounting for linkage disequilibrium