Since 1979, 41 patients with locally advanced thyroid cancers have been prospectively treated in our institution according to a combination regimen of low-dose Adriamycin (doxorubicin) and external-beam radiation therapy. Two types of treatment regimen were used depending on tumor histologic type. Group 1 patients with well-differentiated papillary, follicular, or mixed type tumor (n = 22) received the combined regimen consisting of once weekly administration of Adriamycin (10 mg/m2) before radiation therapy (RT). Radiation therapy was carried out with a daily dose of 200 cGy for 5 days per week to a total tumor dose of 5600 cGy. Group 2 patients with anaplastic giant and spindle cell carcinoma of the thyroid (n = 19) received the combined regimen, consisting of once weekly administration of Adriamycin (10 mg/m2) before hyperfractionated RT. Radiation therapy was carried out with a fractional dose of 160 cGy per treatment twice a day for 3 days per week to a total dose of 5760 cGy in 40 days. Initial complete tumor response rates in the group 1 and 2 were 91% and 84%, respectively. Local tumor control rates at 2 years after combined therapy were 77% and 68%, respectively. The median survival time was 4 years for group 1 and 1 year for group 2. There was no disproportionately enhanced normal tissue morbidity seen with this combined approach. Patients in group 1 have a good quality of life, once the local disease is under control due to the indolent course of the disease. On the contrary, most patients in group 2 promptly developed distant metastases and died from the disease.