To find the dominant epitopes of a major autoantigen in insulin-dependent diabetes mellitus (IDDM), glutamic acid decarboxylase (GAD), we studied the reactivity of peripheral blood T lymphocytes with peptides covering both major isoforms. A significant response to GAD 65 or GAD 67 peptides was detected in 13 of 15 IDDM patients and in 9 of 10 normal controls. Controls most frequently recognised the central region of GAD 65 (residues 161-243). IDDM patients preferentially recognised residues 473-555 (p < 0.03). T-cell responses to GAD 67 peptides were similar in IDDM patients and controls. T lymphocytes from IDDM patients recognise a distinct dominant epitope of GAD, which may be an important target for the disease process.