Multiple sclerosis (MS) is strongly associated with the HLA-Dw2 haplotype DRw15.DQw6 in Caucasoids, although the relative contributions of DR and DQ loci to disease susceptibility are unknown. The situation is further complicated by the apparent lack of an association between DR2 and MS in Orientals. This study examined 42 DR2-positive chromosomes in healthy Chinese and 12 DR2-positive chromosomes in MS patients from Hong Kong, using oligonucleotide hybridizations of DQA1, DQB1, DRB1, and DRB5 polymerase chain reaction (PCR) products. There was marked heterogeneity in DR2-related haplotypes in controls (ten types), where the most frequent haplotype, confirmed in one family, involved the novel arrangement DRB1*1501, DQB1*0601. Another common haplotype had the unusual combination of DRB1*1602, DRB5*0101 as confirmed by DNA sequencing of the DRB5 allele. In contrast, the most common DR2-related haplotype in MS patients was the ‘classical’ Dw2 haplotype DRB1*1501, DQB*0602, with a frequency of 50% compared with 12% in controls (P= 0.01). Novel DR, DO linkage disequilibrium relationship in Hong Kong Chinese have permitted recognition of DQB1*0602 as a susceptibility allele in DR2-positive MS patients, although a role for the DRB1*1501 allele in MS pathogenesis has not been excluded by this study.