DQ8 and DQ2 are associated with susceptibility to and DQ6 with protection from type 1 diabetes mellitus (T1DM). A set of polymorphic genes, called MHC class I chain-related genes (MIC-A) in HLA class I region interact with NK cells. In Italians, MICA allele 5 increases T1DM risk by 6.1. Together with HLA-DQ8 and DQ2 the risk increases severalfold. HLA class I genes, also identified as susceptibility genes for T1DM, interact with polymorphic killer immunoglobulin-like receptors (KIR) on NK cells. HLA-DQ8 and DQ2 and MICA-5 in Swedish and other populations also show positive association with disease. Studies on KIR in Latvian patients with T1DM also suggest a role for KIR in the etiology of T1DM. The results from MICA and KIR studies suggest that polymorphism of these genes of the innate immune system identify possible defects in the first line of antiviral defense in the etiology of T1DM. Screening for these genes could be important in the prediction strategies for T1DM.