Twenty-two subjects in a family with Graves' Disease and 20 normal subjects unrelated to the family were examined for T-cell responses to rec h TSHR-ECD and its synthetic peptides. Seven of the family members and none of the controls responded positively to rec h TSHR-ECD. Peptide 158-176 was the only residue that showed a high percentage of response among family members, no responses in spouses, and a significant difference compared to unrelated controls. Family members under age of 6 did not differ from spouses in response to rec h TSHR-ECD or any individual peptide. Family members ages 6-12 years were significantly different from spouses in response to peptides 30-49, 158-176, and 172-186. The reactivity of adult family members including 3 Graves' patients was significantly different from spouses in response to peptides 44-62, 132-150, 158-176, and 248-263. The responses of female members of the family were higher than that of the male members and significantly different for peptide 272-291. These data suggest that recognition of peptide 158-176 may be an early event in the pathogenesis of the disease and that recognition of both 158-176 and 248-263 residues may be the cornerstone for establishment of the disease.