BACKGROUND Historical outcomes in anaplastic thyroid carcinoma (ATC) are poor, with a median survival of only 5 months and <20% of patients surviving 1 year from diagnosis. We hypothesized that survival in newly diagnosed patients with stages IVA and IVB locoregionally confined ATC might be improved by utilizing an aggressive therapeutic approach, prioritizing both the eradication of disease in the neck and preemptive treatment of occult metastatic disease. METHODS Between January 1, 2003, and December 31, 2007, 25 new ATC patients were evaluated at our institution. Of these 25 patients, 10 (40%) had metastatic disease at diagnosis and therefore underwent palliative treatment, whereas 5 (20%) had regionally confined disease and desired treatment at their local medical facilities. The remaining 10 consecutive patients (40%) had regionally confined ATC and elected aggressive therapy combining individualized surgery (where feasible), intensity-modulated radiation therapy (IMRT), and radiosensitizing + adjuvant chemotherapy intending four cycles of docetaxel + doxorubicin. Outcomes were assessed on an intention to treat basis. RESULTS There were no deaths from therapy, but hospitalization was required in two patients (20%) because of treatment-related adverse events. Five patients (50%) are alive and cancer-free, all having been followed >32 months (range: 32-89 months; median: 44 months) with a median overall Kaplan-Meier survival of 60 months. Overall survival at 1 and 2 years was 70% and 60%, respectively, compared to <20% historical survival at 1 year in analogous patients previously treated with surgery and conventional postoperative radiation at our and other institutions. CONCLUSIONS Although based upon a small series of consecutively treated patients, an aggressive approach combining IMRT and radiosensitizing plus adjuvant chemotherapy appears to improve outcomes, including survival in stages IVA and IVB regionally confined ATC, but remains of uncertain benefit in patients with stage IVC (metastatic) disease. Also uncertain is the optimal chemotherapy regimen to use in conjunction with IMRT. Further multicenter randomized trials are required to define optimal therapy in this rare but deadly cancer.