Background: The purpose of this study was to evaluate the outcome of patients with differentiated thyroid carcinoma whose posttherapy imaging demonstrated I-131 uptake in cervical lymph nodes. Methods: In this prospective cohort study, 95 patients who underwent surgery for well-differentiated thyroid carcinoma had evidence of persistent cervical lymph node metastasis on posttherapy I-131 scintigraphy. These patients were evaluated by subsequent I-131 scintigraphy, and treated with additional I-131 therapy or surgical excision of cervical lymph nodes as clinically indicated. Patients were followed for a mean of 6.8 years. Results: Patients received a total of one to three I-131 administrations (median dosage, 235 mCi). Surveillance I-131 scintigraphy was performed to evaluate disease activity. I-131 uptake was eliminated from the thyroid bed in all patients. Persistent disease was detected in cervical lymph nodes in 9 (9%) of 95 patients, and these 9 patients underwent lymph node excision (1 patient later had recurrent disease and was treated with additional I-131 therapy). All patients subsequently had negative I-131 imaging and undetectable serum thyroglobulin. Of the 95 patients in the study, 9 (9%) developed recurrent disease in cervical lymph nodes. Of these 9 patients, 2 also had distant metastases; 6 of these patients underwent surgical excision of cervical adenopathy, and 3 received additional I-131 therapy. There were no grade >3 toxicities attributable to I-131. At last follow-up, 93 (98%) of the 95 patients were free of disease. Conclusion: Most patients (82%) in the study with cervical lymph node metastases detected on initial posttherapy I-131 scintigraphy were rendered free of disease with I-131 therapy. Surgical reintervention was required in 15% of patients (15/95). The use and timing of additional I-131 therapy versus surgical intervention in this group of patients needs to be further evaluated.