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We investigated the significance of unexpected focal pyriform sinus FDG uptake and determined the ability of PET/CT parameters to identify malignancy.FDG PET/CT reports of 56,585 consecutive subjects were retrospectively reviewed, and 281 cases (0.50%) with focal pyriform sinus uptake were included. PET images were assessed for maximum standardized uptake values (SUVmax) and asymmetric indices of FDG activity, and CT images were evaluated for pyriform sinus narrowing. The final diagnosis was determined by tissue biopsy, laryngoscopy, radiological findings, and clinical follow-up.Among the 281 subjects, final diagnosis was pyriform sinus malignancy in 29 (10.3%) and benignity in 215 cases (76.5%). Malignant lesions had significantly higher SUVmax (9.13 ± 3.64 vs. 3.53 ± 1.01) and asymmetric index (4.16 ± 1.81 vs. 1.54 ± 0.39) compared to benign causes. Patients with malignant lesions also had higher cervical lymph node SUVmax (6.66 ± 8.79 vs. 2.76 ± 2.46, all P < 0.001). Lesion SUVmax ≥4.24 identified malignancy with a sensitivity of 93.1% and specificity of 86.5%. Asymmetric index ≥1.81 had a sensitivity of 100% and specificity of 89.7%.Incidentally identified focal pyriform sinus uptake on FDG PET/CT should be evaluated for possible malignancy in the presence of high SUVmax or asymmetric index.