In the follow-up of patients with differentiated thyroid cancer (DTC), several patients had elevated serum levels of antithyroglobulin antibody (TgAb), undetectable serum thyroglobulin (Tg), and negative radioiodine whole body scan (131I-WBS). We describe the use of neck ultrasonography (US) and fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging in these patients to investigate this clinically challenging problem and propose treating. A total of 49 DTC patients with elevated serum levels of TgAb (>115IU/mL), undetectable Tg and negative 131I-WBS were divided into two groups (positive and negative) according to the neck US findings. Differences in the rate of recurrence between the two groups were investigated. The diagnostic value of 18F-FDG PET/CT in these patients was evaluated. Among the 49 patients, the rate of recurrence of patients with positive neck US was 50%, which was significantly higher than that of patients with negative neck US (17.24%; P=0.014). The sensitivity, specificity, and positive predictive values of 18F-FDG PET/CT imaging in diagnosing the clinical status of these patients were 93.33%, 70.59% and 58.33%, respectively. After the 18F-FDG PET/CT scan, clinical management was changed in 14 patients. Nine patients were operated and five underwent 131I ablation therapy. In the 49 DTC patients with elevated serum levels of TgAb but negative findings in serum Tg and in 131I-WBS, neck US and 18F-FDG PET/CT imaging supported the clinical diagnosis and suggested subsequent treatment.