18F-FDG PET has demonstrated its usefulness in detecting recurrences of differentiated thyroid cancer (DTC) with high thyroglobulin (Tg) levels and negative 131I whole-body scan (WBS); however, the number of patients analyzed is low and different studies report disparate results. To estimate the diagnostic accuracy of 18F-FDG PET in this subgroup of patients. Fifty eight patients (64 18F-FDG PET studies) with histologically proven DTC treated with total thyroidectomy followed by at least one session of 131I therapy for the ablation of thyroid remnants were retrospectively analyzed. Results were verified by pathology, clinical follow-up, response to treatment, or by comparison with conventional diagnostic methods. Sensitivity (Se), specificity (Sp), likelihood ratios (LR), diagnostic accuracy (DA), positive and negative predictive values (PPV, NPV), and Tg levels were calculated for patients with positive and negative 18F-FDG PET results. Twenty seven studies were true positives, 1 false positive, 25 true negatives, and 11 false negatives. Se was 71 %, Sp 96 %, PPV 96.4 %; NPV 69.4 %, DA 81.3 %, positive LR 17.75, and negative LR 0.3. The mean Tg level was 202.34 ng/ml in patients with positive 18F-FDG PET and 40.94 ng/ml in those with negative 18F-FDG PET; the difference between the two groups (161.4 ng/ml) was significant at p <0.05. 18F-FDG PET is a useful for detecting residual or recurrent DTC in patients with elevated Tg and negative 131I WBS.