Whereas most patients with Graves' disease (GD) have antibodies against the thyrotropin receptor, which are measured as thyrotropin-binding inhibitory immunoglobulin (TBII), the TBII of 10% or less of Japanese patients with GD is undetectable at the first visit and throughout the entire clinical course, and these patients tend to respond well to medications and follow the better clinical course. Therefore, the absence of TBII at the first visit may be a predictor of good prognosis. Ninety-seven patients with GD who had remained TBII negative for at least 2 years from the onset, as well as 142 typical TBII-positive GD patients, were examined to reveal the HLA-linked immunogenetic background for this predictor. Compared with a healthy control population, the frequencies of HLA-A*0206 (OR=2.17, p=9.73x10(-4)) and DPB1*0501 (OR=3.26, p=3.31x10(-7)) carriers were increased in the typical patients, whereas those of HLA-A*0201 (OR=2.16, p=1.92x10(-3)), A*0207 (OR=3.19, p=7.17x10(-4)), and DPB1*0202 (OR=3.13, p=3.97x10(-4)) were increased in the TBII-negative group. These two patient groups were associated with similar HLA-A alleles and different HLA-DPB1 alleles, suggesting the presence of two genetic factors for GD within the HLA region; one is HLA-A linked and may be related to thyroid organ specificity, the other is HLA-DP linked and may control the severity of autoimmunity.