We studied the psychological performance and the quality of life in patients with differentiated thyroid carcinoma, either during treatment with chronic suppressive doses of levothyroxine, or during the withdrawal of levothyroxine needed to perform whole-body scanning with radioactive iodine, with those of appropriate healthy controls. Eighteen women with differentiated thyroid carcinoma and 18 euthyroid age-matched healthy women were recruited. Patients were studied the day before levothyroxine withdrawal (when in chronic mild or subclinical hyperthyroidism), 4-7 days later (when most patients had normal serum free thyroxine and free triiodothyronine levels), and the day before scanning (when in profound hypothyroidism). Controls were studied at one time point. When compared with controls, patients presented with impairment of several indexes during chronic suppressive levothyroxine therapy (total score, emotional, sleep, energy and social of the Nottingham Health Profile; mental health, general health and social function of the SF-36, and total score on Wais Digit Span; P<0.05 for all comparisons). Also, quality of life indexes (19 of 21 scores), cognitive tests (6 of 12 scores), and affective and physical symptoms visual mental scales (18 of 19) worsened during profound hypothyroidism (P<0.05 for all comparisons). Quality of life and cognitive performance were almost comparable with those of euthyroid controls when most patients had normal free thyroxine and triiodothyronine levels. In conclusion, quality of life and psychometric functionality in patients with differentiated thyroid carcinoma is not only affected by withdrawal of levothyroxine but also by long-term treatment with supraphysiological doses of levothyroxine.