Six patients with very severe forms of non-rapid cycling bipolar affective illness whose symptoms had previously been refractory to all current antidepressant and/or prophylactic medications were treated with supraphysiological doses of thyroxine (250 to 500 micrograms/day) as an adjuvant to their previous medications. The mean follow-up period was 27.8 +/- 12.8 months (range 12 to 46). The mean number of relapses during the follow-up period of each patient declined from 5.3 +/- 3.1 to 0.8 +/- 0.8 and the mean duration of hospitalization from 10.0 +/- 5.6 to 0.8 +/- 1.2 months as compared to the same length of time for each patient before the start of treatment with high-dose thyroxine (T4). Three of the patients had no further relapses at all. Thus, for these patients, who had previously been severely ill and therapy-resistant, high-dose T4 administration proved to have excellent effects on the course of the illness. However, in five of these patients the effect of the T4 was strong enough only when it was administered in combination with a prophylactic and antidepressant and/or neuroleptic drug, of which in some cases high doses were also needed. The side effects were negligible. Mechanisms that may possibly underlie the beneficial effects of high-dose T4 in bipolar affective disorder are discussed.