T-cell receptor alpha- and beta-chain polymorphisms have been investigated in patients with autoimmune thyroid disease. Using a cDNA probe for the T-cell receptor alpha chain, a 1.4-kb V alpha Taq I restriction fragment was found in 25 of 33 patients with autoimmune hypothyroidism compared to 33 of 61 control subjects (p less than 0.05) and 16 of 43 patients with Graves' disease (p less than 0.001 compared to patients with autoimmune hypothyroidism). Moreover, when Graves' patients were divided according to HLA-DR3 status, there was a significantly reduced frequency of the 1.4-kb V alpha fragment in HLA-DR3-negative patients (p less than 0.05 compared to controls). There was no significant association of either thyroid disorder with polymorphisms of the T-cell receptor alpha- or beta-chain-constant region genes, after Taq I and Bgl II digestion, respectively. These results show that inherited variation in T-cell receptor genes, recognizable before any somatic event has taken place, may play a role in susceptibility to autoimmune disease.