Eleven patients with rapid cycling bipolar affective disorder whose symptoms were refractory to their current medication regimen were entered into an open trial of high-dose levothyroxine sodium added to a stable regimen of those medications. At baseline, all patients exhibited a rapid cycling pattern and were evaluated prospectively through at least one affective episode. Levothyroxine was added to the baseline medication regimen, and the dosage was increased until clinical response occurred or until side effects precluded further increase. While patients were taking levothyroxine, scores on both depressive and manic symptom rating scales decreased significantly compared with baseline. This improvement was due to the clear-cut response of depressive symptoms in 10 of 11 patients, with manic symptoms responding in five of the seven patients who exhibited them during baseline evaluation. Four patients then underwent single- or double-blind placebo substitution; three patients relapsed into either depression or cycling. Treatment response did not depend on previous thyroid status. In 9 of 10 responsive patients, supranormal circulating levels of free thyroxine were necessary to induce clinical response. Side effects were minimal, and there were no signs or symptoms of levothyroxine-induced hypermetabolism.