Antiepileptic drugs (AEDs) may affect serum thyroid hormone concentrations. This prospective, randomized study evaluated thyroid function in men and women with epilepsy both before and after double-blinded withdrawal of AED monotherapy, and assessed whether any changes were reversible. One hundred sixty patients were randomized to withdrawal and nonwithdrawal groups; 150 patients completed the intervention and were included in the 12-month study. Serum samples were obtained from 130 patients, from before and 4 months after intervention. Following AED withdrawal, significant increases in free thyroxine (FT(4)) serum concentrations were measured in men and women treated with carbamazepine. In women treated with valproate, serum concentrations of free triiodothyronine (FT(3)) decreased significantly in the withdrawal group. Thus, for both men and women with epilepsy, carbamazepine treatment reduces serum FT(4) concentrations, but valproate treatment of women with epilepsy increases serum FT(3.) Our study demonstrated that these changes can be reversed by treatment withdrawal, even after years of treatment.