Multiple Sclerosis (MS) is a demyelinating disease associated with the HLA‐DR2‐related haplotype DRB1*1501, DQB1*0602 in Caucasoids and with DQB1*0602 in DR2‐positive Cantonese. However, many MS patients do not have the high‐risk HLA‐D determinants and alternative genes may contribute to the pathogenesis of MS. One candidate gene is HLA‐DPB1. Our reanalysis of five earlier reports of HLA‐DPB1 antigen distributions in Caucasoid MS patients shows a consistent and highly significant increase (p = 1.5 × 10‐5) in frequency of HLA‐DPw3 in the combined data set. This study tests whether HLA‐DPw3 (DPB1*0301) is also increased in frequency in Australian and Cantonese MS patients and whether any distortion in DPB1 allelic distributions can be attributed to linkage disequilibrium with DQB1*0602. PCR‐RFLPs were used to determine distributions of 20 HLA‐DPB1 alleles in 41 Australian MS patients and 67 controls of known DQB1*0602 status and in 11 Cantonese MS patients and 33 controls positive for HLA‐DR2. HLA‐DP distributions in Australian MS patients and controls positive for DQB1*0602 did not differ, but in those MS patients lacking DQB1*0602, the DPB1*0301 antigen (phenotype) frequency was significantly (p = 0.006) increased (50.0%) when compared with DQB1*0602‐negative controls (9.1%). DPB1*0301 was associated (p = 0.003) with DQB1*0402 (DR8) in Caucasoid MS patients. In Cantonese MS patients positive for DQB1*0602, there was an increase in frequency of DPB1*0201 (66.7%) compared with HLA‐DR2‐positive controls negative for DQB1*0602 (10.0%), possibly due to linkage disequilibrium (p = 0.06) with the DRB1*1501, DQB1*0602 haplotype. In DR2‐positive Cantonese lacking DQB1*0602, DPB1*1301 was increased in MS patients (80%) when compared with controls (13.3%) although the association did not reach statistical significance when the p value was corrected for multiple comparisons; the increase could not be accounted for by linkage disequilibrium with any HLA‐DR2‐related haplotypes. This study suggests that the HLA‐DPB1 locus, or a closely‐linked locus, may contribute to inherited susceptibility for MS in those lac