There are two peaks in the distribution of the age of onset of type 1 diabetes mellitus (T1DM)--the first in early childhood and the second at the time of puberty. Although T1DM results from the interaction of genetic and non-genetic factors, it has not been established which factors contribute to the bimodal distribution. The genetic component of T1DM is in large part related to genes from the human leukocyte antigen (HLA) complex (IDDM1); however, loci from the variable nucleotide tandem repeat (VNTR) region of the insulin (INS) gene (IDDM2) and more recently, the cytotoxic T-lymphocyte-associated protein-4 region (CTLA4, IDDM12) have also been implicated. Therefore, we examined the potential interaction between these loci through the influence of the age of onset of T1DM in diabetic and control Caucasian individuals. We discovered that younger individuals with HLA-DRB1*0301/DRB1*04 and INS I/I genotypes exhibited increased susceptibility to T1DM, whereas the interaction of INS I/I and CTLA4 G/G genotypes was more common in older children with T1DM. Combining the age of onset of T1DM with specific genotypes may operate to produce a single disease through different underlying causes.