Chemotherapy represents the only therapeutic option in most poorly differentiated thyroid carcinomas, although its effect is limited and short lasting. The aim of this study was to evaluate whether increasing the metabolic rate of thyroid cancer cells by TSH stimulation might result in higher response rate to chemotherapy. Fourteen patients with poorly differentiated thyroid carcinoma and nonfunctioning diffuse lung metastases detected at computed tomography scan, entered this study. A combination of carboplatinum and epirubicin was administered at 4- to 6-wk intervals for six courses. TSH stimulation was achieved by reduction of the daily dose of L-thyroxine resulting in mild hypothyroidism (eight patients) or by administration of recombinant human TSH (six patients). Two additional patients did not complete the therapeutic protocol due to severe hematological side effects. Results were evaluated by comparison of lung computed tomography scans before and after therapy. One patient had a complete remission. Five patients had partial remission, and seven patients had disease stabilization. One patient progressed to death. The overall rate of positive responses was 37% that rose to 81% when including patients with stable disease. Serum thyroglobulin after chemotherapy declined more than 50% in six patients, with respect to basal levels. Apparently, no difference in the response rate was observed between exogenous or endogenous TSH stimulation. At the time of this analysis, among the patients who completed the treatment courses, 9 of 14 patients (64.3%) are still alive (median survival from start of chemotherapy = 21 months, range: 15-34). Six of these patients did not show progression of lung disease, whereas regrowth of lung metastases was observed in three patients after 19, 20, and 21 months from chemotherapy, respectively. Five patients died of their disease, including the one who had progression of lung disease during chemotherapy, three who died for brain or bone metastases, and one who died for refractory local tumor invasion. No progression of lung metastases was observed until death in these four patients. In conclusion, the response rate of poorly differentiated thyroid cancer to chemotherapy observed in this study was favorable and promising. TSH stimulation may have contributed to these results.