Behçet's disease is known to be associated with HLA-B51. To address the possibility that a non-human leukocyte antigen (HLA) gene closely linked to the HLA-B gene, such as tumor necrosis factor (TNF)-alpha, TNF-beta, or ECl (the locus that determines the susceptibility to alloreactive natural killer [NK] cells), is involved in the susceptibility to Behçet's disease, NcoI and EcoRI restriction fragment length polymorphisms in the TNF-beta gene and the susceptibility to lysis by alloreactive NK cells were investigated in Behçet's patients. In our NcoI restriction fragment length polymorphism (RFLP) analysis in the TNF-beta gene, the frequency of the NcoI 5.5 kb homozygote was decreased considerably in the patients, especially those with the ocular lesions, in relation to the healthy controls. However, no significant difference was observed between these groups in the EcoRI RFLP band distribution in this gene or the in susceptibility to lysis by alloreactive NK cells. These results indicated that a non-HLA gene located around the TNF gene region centromic of the HLA-B gene was a candidate to control the genetic susceptibility to Behçet's disease.