The major autoantigens in Addison's disease have recently been shown to be members of the adrenal steroidogenic enzymes, such as 21OH. The genes encoding the 21OH enzyme are located in the class III segment of the MHC complex. Therefore, its identification as an autoantigen provides a novel link between MHC and susceptibility to this autoimmune disease. We have determined the MHC class II (DRB1, DQA1, DQB1, DPB1) and class III (TNF, HSP70, C4, 21OH) gene polymorphism in patients with Addison's disease. Also, we tested whether presence of autoantibodies against 21OH is associated with specific alleles in MHC. Our results show that patients with Addison's disease in association with APS2 or Addison's disease as an isolated form share highly similar MHC class II and class III alleles. A very strong association with HLA DRB1*0301, DQA1*0501, DQB1*0201, and DPB1*0101, as well as with the C4A + 21OHA gene deletion and TNFB*1 allele was observed. However, identical gene markers were observed also in controls matched for DRB1*0301, thus suggesting that the patient group did not carry MHC gene segments specific for Addison's disease. The presence of autoantibodies against 21OH was not found to be directly determined by the MHC alleles; rather it was associated with the clinical form of the disease.