Radioactive iodine (131I) is an important therapeutic option for the treatment of metastatic thyroid carcinoma. Survival in patients with metastases that concentrate radioiodine is better than those whose metastatic lesions do not take up radioiodine. Survival is markedly reduced in patients who have metastatic lesions that concentrate 18F-fluorodeoxyglucose (FDG) on positron emission tomography (PET). In this retrospective study, we evaluated the ability of 131I to destroy FDG-avid metastatic lesions in thyroid cancer patients. Twenty-five patients with positive FDG-PET scans received at least one dose of 131I treatment before a second FDG-PET was performed. The average interval between the two PET scans was 12.9 months. The average interval between the 131I treatment and the follow-up FDG-PET was 10.1 months. We measured posttherapy changes in lesional volume, in standard uptake values (SUV) of FDG, and in serum thyroglobulin (Tg) levels. The total volume of FDG-avid metastases rose significantly (p = 0.036) from a mean of 159 mL to 235 mL after 131I therapy, the maximum SUV rose from 9.3 to 11.9, the median Tg at the time of the second PET scan was 132% of that at baseline. Statistical analyses demonstrated no significant changes in maximum SUV, or serum Tg levels after 131I in the FDG-PET-positive group. In a control group of FDG-PET-negative patients, the serum Tg decreased to 38% of baseline after 131I therapy (p < 0.001). We conclude that high-dose 131I therapy appears to have little or no effect on the viability of metastatic FDG-avid thyroid cancer lesions.