Selective pituitary resistance to thyroid hormone (PRTH) is responsible for thyrotoxicosis due to inappropriate secretion of TSH. The TSH suppressive action of D-thyroxine (DT4) has been previously documented in euthyroid and hypothyroid subjects. This prompted us to treat with DT4 three patients with PRTH uncontrolled by anti-thyroid drugs (ATD) alone or supplemented with bromocriptine, and whose follow-up had been complicated by atrial fibrillation in two patients. Because of 100% cross-reactivity between the D and L isomers of T4 and T3 in our RIAs, thyroglobulin (Tg) was used as an index of thyroid secretion. Under ATD, TSH and Tg levels were respectively: 35 mIU/l and 670.5 pmol/l (patient 1), 87 mIU/l and 453 pmol/l (patient 2) and 110 mIU/l and 906 pmol/l (patient 3). When DT4 was added (patient 1, 3 mg daily; patients 2 and 3, 2 mg daily) to the same dose of ATD, plasma TSH and Tg levels fell but were still over the upper limit of normal and thyrotoxicosis persisted as illustrated by a recurrence of atrial fibrillation in one patient. When ATD were withdrawn and DT4 given alone (2 mg daily) all symptoms subsided within 1 month while TSH and Tg levels fell within the normal range. TSH normalization was documented within 1 week in one patient.(ABSTRACT TRUNCATED AT 250 WORDS)