Rationale and Objectives. The effectiveness of 18-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) and technetium-99m tetrofosmin (Tc-99m TF) single photon emission computed tomography (SPECT) of neck and chest was evaluated to detect metastatic lesions in well-differentiated thyroid carcinoma after nearly total thyroidectomy and radioiodine (I-131) treatment who present with elevated serum human thyroglobulin levels but negative I-131 whole body scan. Materials and Methods. Twenty-three patients with differentiated thyroid carcinoma who underwent nearly total thyroidectomy and I-131 treatments were included in this study. Results. All of the 23 patients had negative I-131 whole body scan and elevated human thyroglobulin levels under thyroid-stimulating hormone stimulation. Metastatic lesions were detected by FDG-PET in 20 patients, while Tc-99m TF SPECT revealed metastatic lesions in only 11 of the 20 patients. Both FDG-PET and Tc-99m TF SPECT failed to demonstrate miliary pulmonary metastases in two of the remaining three patients. The other patient did not show any lesion on FDG-PET, Tc-99m TF SPECT, chest computed tomography, or other imaging techniques. Conclusion. This study demonstrated that FDG-PET is more sensitive than Tc-99m TF SPECT to detect metastatic lesions in differentiated thyroid carcinoma with elevated human thyroglobulin but negative I-131 whole body scan. However, miliary pulmonary metastases could be missed by the both techniques.