We have tested the possible association of HLA-DQB and HLA-DPB alleles with Graves' thyrotoxicosis, with or without severe ophthalmopathy, by polymerase chain amplification of genomic DNA and allele-specific oligonucleotide probing. There was no significantly abnormal distribution of DQB alleles compared to 50 control subjects except for a reduced prevalence of DQw 3.1 in the Graves' patients with severe ophthalmopathy (X2 = 6.23, P less than 0.02). HLA-DPB 2.1/8 was found in only 1 of 40 of these patients compared with 15 of the controls (X2 = 11.49, P less than 0.001). Ten of 48 patients with Graves' disease but without clinically significant eye involvement were HLA-DPB 2.1/8 positive, not significantly different from controls, but significantly different from the ophthalmopathy group (X2 = 6.70, P less than 0.01). The other DPB alleles in both groups of Graves' disease patients were the same as controls. These results suggest that HLA-DPB 2.1/8 may confer a protective effect in Graves' disease with respect to ophthalmopathy.