The major locus for multiple sclerosis (MS) susceptibility is located within the class II region of the Major Histocompatibility Complex (MHC). HLA-DRB1 alleles, constituting the strongest MS susceptibility factors, have been widely exploited in research including construction of transgenic animal models of MS. Many studies have concluded that HLA-DRB1 * 15 allele itself determines MS-associated susceptibility. If this were true, haplotypes bearing this allele would confer equal risk. If HLA-DRB1 * 15 bearing haplotypes differed for risk, roles for other loci in this region would be implied and further study of the fine structure of this locus would be compelling. We have tested the hypothesis comparing haplotypes stratified by HLA class I tagging. We show here that HLA-DRB1 * 15 -bearing-haplotypes in 1970 individuals from 494 MS families are indeed heterogeneous. Some HLA-DRB1 * 15 haplotypes determine susceptibility while others do not. Three groups of class I tagged HLA-DRB1 * 15 haplotypes were not over-transmitted: ( i ) HLA-DRB1 * 15-HLA-B * 08 (TR = 25, NT = 23, Odds Ratio = 1.09), ( ii ) -HLA-B * 27 (TR = 18, NT = 17, Odds Ratio = 1.06), and ( iii ) rare HLA-DRB1 * 15 haplotypes (frequency <0.02). Rare haplotypes were significantly different from common haplotypes, and transmissions were remarkably similar to those for class-I-matched non- HLA-DRB1 * 15 haplotypes. These results unambiguously indicate that HLA-DRB1 * 15 is part of a susceptibility haplotype but cannot be the susceptibility allele itself, requiring either epistatic interactions, epigenetic modifications on some haplotypes, or nearby structural variation. These findings strongly imply that differences among HLA-DRB1 * 15 haplotypes will furnish the basis for MHC-associated susceptibility in MS and raise the possibility that the MHC haplotype is the fundamental unit of genetic control of immune response.