ObjectivesPositron emission tomography-computed tomography (PET/CT) with fluorine-18-fluorodeoxy-D-glucose (FDG) has evolved from a research modality to an invaluable tool in head and neck cancer imaging. However, interpretation of FDG PET/CT studies may be difficult due to the inherently complex anatomical landmarks, certain physiological variants and unusual patterns of high FDG uptake in the head and neck. The purpose of this article is to provide a comprehensive approach to key imaging features and interpretation pitfalls of FDG-PET/CT of the head and neck and how to avoid them.MethodsWe review the pathophysiological mechanisms leading to potentially false-positive and false-negative assessments, and we discuss the complementary use of high-resolution contrast-enhanced head and neck PET/CT (HR HN PET/CT) and additional cross-sectional imaging techniques, including ultrasound (US) and magnetic resonance imaging (MRI).ResultsThe commonly encountered false-positive PET/CT interpretation pitfalls are due to high FDG uptake by physiological causes, benign thyroid nodules, unilateral cranial nerve palsy and increased FDG uptake due to inflammation, recent chemoradiotherapy and surgery. False-negative findings are caused by lesion vicinity to structures with high glucose metabolism, obscuration of FDG uptake by dental hardware, inadequate PET scanner resolution and inherent low FDG-avidity of some tumours.ConclusionsThe interpreting physician must be aware of these unusual patterns of FDG uptake, as well as limitations of PET/CT as a modality, in order to avoid overdiagnosis of benign conditions as malignancy, as well as missing out on actual pathology.Teaching points• Knowledge of key imaging features of physiological and non-physiological FDG uptake is essential for the interpretation of head and neck PET/CT studies.• Precise anatomical evaluation and correlation with contrast-enhanced CT, US or MRI avoid PET/CT misinterpretation.• Awareness of unusual FDG uptake patterns avoids overdiagnosis of benign conditions as malignancy.