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The aim of this study was to investigate the clinical importance of incidental focal or diffuse fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in the thyroid gland on positron emission tomography (PET)/computed tomography (CT) and to evaluate the additive value of thyroid ultrasonography (US) in defining the malignancy potential of thyroid incidentalomas.A total of 1450 patients, who had undergone a PET/CT scan for staging or restaging of various malignancies, were screened retrospectively and 52 (3.6%) patients with focal or diffuse 18F-FDG uptake in the thyroid gland on PET/CT were enrolled in the study. None of the patients had any history of thyroid diseases. Thyroid US with elastography for a thyroid nodule was performed for all the patients cross-sectionally. Thyroid fine-needle aspiration biopsy (FNAB) was also applied at the same time as the thyroid US to 34 patients with a nodule(s) 10 mm or more in diameter or less than 10 mm, but with malignancy potential ultrasonographically. The cytology results were compared with the thyroid US and 18F-FDG PET/CT findings.Although 39 patients had focal (group 1) 18F-FDG uptake in the thyroid gland, the remaining 13 patients had diffuse (group 2) uptake. In group 1, FNAB was performed in 32 patients. In 10 of 32 (31%) patients, FNAB results were concordant with malignant cytology (seven primary thyroid malignancy and three metastasis to thyroid). In group 2, in one of two patients who had undergone FNAB, malignant cytology (metastasis to thyroid) was detected. Although the difference between the maximum standardized uptake value (SUVmax) of malignant and benign nodules was statistically significant (10.2±8.9 vs. 5.6±3.0, P=0.013), the difference between the nodule sizes was not statistically significant (20.0±7.3 vs. 16.7±7.4, P=0.923). The presence of suspicious US findings and a high elastography score (≥4) were also statistically significant (P<0.001 and P=0.035, respectively). In the receiver–operator characteristic analysis, a 5.3 cut-off SUVmax was calculated with 82% sensitivity and 65% specificity for predicting malignant cytology.Focal 18F-FDG uptake was associated with a higher prevalence of malignant thyroid nodule compared with diffuse 18F-FDG uptake. In particular, if a focal thyroid incidentaloma with high SUVmax (>5.5), suspicious US findings, and a high elastography score (≥4) is detected, a pathological diagnosis, either by histology or by cytology examination, should be made, especially when the patient has a long life expectancy.