Hodgkin's disease (HD) is a complex lymphoma-like disease which occurs as four main subtypes, nodular sclerosing (NS), mixed cellularity (MC), lymphocyte predominant (LP) and lymphocyte depleted (LD). Suggestions from epidemiological studies that HD may represent an unusual response to infection imply that the lack of previous response could be due to genetic factors. Following recent reports suggesting that there is an increased frequency of HLA-DPB1*0301 in Hodgkins disease, we have studied DPB1 in two series of patients using molecular typing methods. One series is a retrospective group of 118 patients over the age of 15 years from a single centre, and the other is a multi-centre prospective group of 45 patients between the age of 16 and 24 years. In both series, the percentage of HD patients with DPB1*0301 is greater than in the controls, confirming that this seems to be an HD-susceptibility allele. However, extension of the analysis in relation to HD subtype shows that the increase in *0301 is present in nodular sclerosing (NS), mixed cellularity (MC) and lymphocyte predominant patients (LP) HD patients, but preliminary evidence suggests an increase in *0401, and possibly *0501 in MC- and LP-HD. The DPB1 hypervariable region (HVR) amino-acid motif Asp55, Glu56 (*0301-like, HVR-C) is increased in NS compared with non-NS (ie MC+LP), whereas the frequency of Ala55, Ala56 (*0401-like) is increased in non-NS compared with NS. Conversely, Asp84, Glu85Ala86(*0301-like, HVR-F) motif is more frequent in NS than non-NS patients, but there is no increase in Gly84, Gly855, Pro86 (*0401-like). These findings suggest that genetic susceptibility in HD may reside at the level of HVR-encoded DPB1 peptide-binding residues, rather than with a specific allele, and that this may in some way influence the HD subtype.