The role of adjuvant external-beam radiation therapy (EBRT) in well-differentiated thyroid cancer is not well delineated. Many clinicians rely solely on iodine 131 (131I) to destroy thyroid remnants following thyroidectomy. However, the lesser uptake of isotope in tumor cells suggests that 131I alone may not be sufficient to eradicate microscopic residual disease when no gross thyroid tissue remains. We conducted a retrospective study to examine the potential benefit of adjuvant EBRT in patients at high risk for microscopic residual disease following thyroidectomy. Between 1973 and 2001, 44 patients with well-differentiated papillary or follicular thyroid cancer were found to have extracapsular extension following thyroidectomy. These patients were divided into 2 groups based on the type of treatment; 11 patients had received adjuvant EBRT (with or without 131I) and 33 patients had not received EBRT (i.e., they received adjuvant 131I only). We reviewed their medical records and compiled data on local recurrence and overall survival (Kaplan-Meier analysis). Despite having a less favorable prognosis, the EBRT group experienced no local recurrences during a mean follow-up of 7.8 years; in contrast, 9 local recurrences were seen in the no-EBRT group. Also, the median survival for patients without a local recurrence was longer than that for those who had failed locally (425 vs. 317 mo). Although our population was not large enough for these differences to achieve statistical significance, our study did show that adjuvant EBRT provided excellent results. We hypothesize that a reciprocal irradiation effect between cancer cells and normal cells may be necessary in order for 131I to be tumoricidal. If so, a patient with microscopic residual disease would not have enough cancer cells to sufficiently concentrate 131I. Because EBRT does not depend on such a mechanism, it may be more effective than 131I in controlling disease in the setting of microscopic disease. Larger studies are needed to validate our results. In the meantime, we believe that adjuvant EBRT should play an important role in the treatment of patients with high-risk well-differentiated thyroid cancer.