Patients on long-term treatment with either of the stereochemically related antiepileptic drugs phenytoin (DPH) or carbamazepine (CBZ) had similar changes in serum thyroid hormone concentrations. T4, FT4, FT4 index, T3, FT3, FT3 index and rT3 were reduced, whereas T3U and TSH were not significantly different from the reference group levels. Long-term phenobarbitone treatment had no convincing effect on the investigated parameters when used alone, but possibly potentiated the effect of CBZ. In patients starting on CBZ, T4 fell to a stable 70% of the basal level after 1--2 weeks. T3 decreased transitorily to 85% of the basal level. TSH showed a complementary but somewhat delayed transitory increase. T3U and TBG did not change significantly. The effect of CBZ and DPH can be explained by interference with thyroid hormone binding to TBG combined with enzyme-induced increased metabolic clearance rate of thyroid hormones without homeostatic maintenance of premedication levels of FT4 and FT3. We suggest that the regulated factor maintaining euthyroidism in these patients is the total quantity of thyroid hormones being degraded in the tissues per unit time. We conclude that serum concentrations of FT4 and FT3 do not reflect thyroid status adequately under all circumstances.