Human leucocyte antigen (HLA)-DRB1*15 is associated with predisposition to multiple sclerosis (MS), although conjecture surrounds the possible involvement of an alternate risk locus in the class I region of the HLA complex. We have shown previously that an alternate MS risk allele(s) may be encompassed by the telomerically extended DRB1*15 haplotype, and here, we have attempted to map the putative variant. Thirteen microsatellite markers encompassing a 6.79-megabase (D6S2236-G51152) region, and the DRB1 and DQB1 genes, were genotyped in 166 MS simplex families and 104 control families from the Australian State of Tasmania and 153 narcolepsy simplex families (trios) from the USA. Complementary approaches were used to investigate residual predisposing effects of microsatellite alleles comprising the extended DRB1*15 haplotype taking into account the strong predisposing effect of DRB1*15: (1) Disease association of the extended DRB1*15 haplotype was compared for MS and narcolepsy families--predisposing effects were observed for extended class I microsatellite marker alleles in MS families, but not narcolepsy families; (2) disease association of the extended DRB1*15 haplotype was investigated after conditioning MS and control haplotypes on the absence of DRB1*15--a significant predisposing effect was observed for a 627-kb haplotype (D6S258 allele 8-MOGCA allele 4; MOG, myelin oligodendrocyte glycoprotein) spanning the extended class I region. MOGCA allele 4 displayed the strongest predisposing effect in DRB1*15-conditioned haplotypes (p = 0.0006; OR 2.83 [1.54-5.19]). Together, these data confirm that an alternate MS risk locus exists in the extended class I region in Tasmanian MS patients independent of DRB1*15.