It is known that certain combinations of alleles within the Human Leukocyte Antigen (HLA) Complex are associated with susceptibility or resistance to insulin-dependent diabetes mellitus (IDDM). The association of DR and DQ with IDDM has been well documented. Even though the association of specific DP alleles with some autoimmune diseases (i.e. juvenile rheumatoid arthritis [JRA] and celiac disease) has already been demonstrated, the role of HLA-DP genes in IDDM remains uncertain. A previous study conducted on a group of diabetic Venezuelan families with IDDM proband demonstrated that the HLA-DRB1*04-DQA1*03-DQB1*0302 and DRB1*03-DQA1*0501-DQB1*0201 combinations present a strong association with susceptibility to IDDM. The availability of this population enabled us to assess further susceptibility associated with other HLA class II alleles. We analysed HLA-DPA1 and DPB1 genes of 42 Venezuelan families with one IDDM proband and of 32 healthy families by oligotyping (PCR-SSO) using primers and probes from the XIth Histocompatibility Workshop. In contrast with previous data reported in other populations, the HLA DPA1*01-DPB1*0202 was the only haplotype significantly associated with IDDM in the Venezuelan population studied. In most cases the data showed this HLA DP allele combination as a part of the HLA DRB1*03-DQA1*0501-DQB1*0201 haplotype positively associated with IDDM, indicating a linkage disequilibrium between the alleles involved in this HLA DR-DQ-DP haplotype and as a consequence, a secondary role of HLA-DP genes in conferring susceptibility to the development of the disease. The analysis also indicates a non-significant increase of HLA DPA1*01-DPB1*0301 and DPA1*02-DPB1*1301 haplotypes among diabetics. However, both combinations were in 50% of the cases associated with the HLA DRB1*04-DQA1*03-DQB1*0302 haplotype. These data and their comparison with HLA DR-DQ-DP haplotypes in more homogeneous ethnic groups support the existence of a weak association of IDDM with specific HLA DP alleles and indicate how the distribution of these DP alleles could differ depending on the ethnic groups studied.