There is convincing evidence that certain combinations of alleles within the human leucocyte antigen (HLA) complex, particularly within HLA-DQ, are associated with either resistance or susceptibility to insulin-dependent diabetes mellitus (IDDM). A previous study conducted on a large, well-defined group of patients demonstrated that DQB1*0302 (DQw8) conferred 'dominant susceptibility' to IDDM while DQB1*0602 (DQw1.2) conferred 'dominant protection'. The availability of this population enabled us to further assess susceptibility associated with other class II alleles in an effort to map an outside HLA boundary of disease association. Using a group-specific polymerase chain reaction protocol and a series of oligonucleotide probes which define over twenty DP beta alleles, we studied 286 unrelated Caucasian patients with IDDM and 184 normal subjects. We found that while several alleles are increased (DPB1*0201, DPB1*0301, DPB1*0402) or decreased (DPB1*0101, DPB1*0202) in the diabetic population compared with the normal subjects, the HLA association with IDDM is considerably weaker at the DP locus. These data define the centromeric boundary for the HLA-associated susceptibility gene in IDDM, localizing susceptibility to the region telomeric to HLA-DP up to and including HLA-DQ.