Although association between multiple sclerosis (MS) and HLA-DR2,DQw6 has been well documented, family studies have not established linkage to HLA. Here we have (1) carried out an HLA-DQA1, -DQB1 association study in unrelated patients and controls, and (2) analyzed linkage between MS and HLA in multiplex families using both nonparametric and parametric methods. The subjects and families were derived from the genetically homogeneous Finnish population, and 14 of the 21 families came from a high-risk area with exceptional familial clustering of cases. In the association study, the frequencies of the alleles DQA1*0102 and DQB1*0602 (encoding DR2-associated DQw6 antigen) were significantly increased in MS patients compared to controls. In the families, we observed that the segregation of MS with DQA1*0102 and DQB1*0602 was not HLA haplotype specific, i.e., these alleles were frequently transmitted to MS relatives on different parental haplotypes. Consequently, we found strong evidence for linkage between MS and HLA only when the haplotype-independent segregation of the MS-associated alleles was controlled. This observation may partially explain the lack of linkage evidence in previous family studies. The highest LOD scores were obtained to the DQA1 locus (LODmax = 6.43, theta = 0.00). The linkage analyses suggest that both the patients' HLA haplotypes may contribute to MS susceptibility. In one of a patient's haplotypes, the susceptibility locus was closely associated with DQA1*0102 and DQB1*0602, whereas in the other haplotype no association with any of the individual candidate loci was found. These results demonstrate, for the first time, a close linkage between MS and HLA, and raise the possibility of distinct HLA-linked susceptibility genes in MS.