The natural course of hyperthyroidism due to Graves' disease after discontinuation of antithyroid drug therapy was studied in 184 patients who had been treated with methimazole and whose thyroid function was suppressible with T3 when methimazole was discontinued. The patients were followed after discontinuation of therapy for up to 60 months. Serum T4, free T4 (FT4) and T3 levels, TSH receptor antibody (TRab) and anti-DNA antibody titers, and the percentage of HLA-DR positive lymphocytes in peripheral blood were measured serially. TRab and anti-DNA antibody tests were positive in the majority of patients before treatment and were negative in most at the end of treatment. Twenty-three (12.5%) patients had a recurrence of their hyperthyroidism, which occurred a mean of 20 months after withdrawal of methimazole; they are designated as having overt recurrent hyperthyroidism (group A). In these patients, serum T4, FT4 and T3 concentrations increased rather abruptly to markedly elevated levels in a several-month period and the TRab and anti-DNA antibody titers increased markedly at or shortly after recurrence in the majority. In 9 patients (4.1%), TRH-induced TSH secretion became totally suppressed, indicating the reappearance of thyroidal autonomy; however, the patients did not have any hyperthyroid signs and symptoms (subclinical hyperthyroidism; group B). Their serum T4 and FT4 concentrations fluctuated in the upper normal to slightly supra-normal range, and their serum T3 concentrations remained within the normal range throughout the follow-up period, but their TRab and anti-DNA antibody titers did not appreciably increase. Thus, the time of recurrence could not be precisely determined in group B. In the remainder (152 patients; 83.4%), serum thyroid hormone levels and TRH-induced TSH secretion remained normal, TRab and anti-DNA antibody titers remained negative, and hyperthyroidism did not recur (euthyroid remission; group C). At the time of final examination (in groups B and C) or at the time of recurrence (in group A), the percentage of HLA-DR positive peripheral lymphocytes was 17.9% in group A, 15.9% in group B, and 12.1% in group C. Retrospective analysis of the data indicated that the mean pretreatment TRab titer (percent inhibition of TSH binding) was slightly but not significantly lower in group C (37.8%) compared to those in group A (53.9%) and group B (54.8%). The 3 groups were indistinguishable by all other laboratory data both before treatment and at the time of the T3 suppression test. These data strongly indicate heterogeneity among patients with hyperthyroidism due to Graves' disease.(ABSTRACT TRUNCATED AT 400 WORDS)