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Objective: The objective of this study was to assess the clinical value of 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) after the first cycle of induction chemotherapy (IC) in locally advanced squamous cell carcinoma of the head and neck (LASCCHN). Methods and findings: A prospective, single-arm, single center study was performed, with patients enrolled between February 2010 and July 2013.Patients (n = 49) with stage III/IVA–B LASCCHN who underwent IC with taxanes, cisplatin, and fluorouracil were recruited. Staging procedures included loco-regional and chest imaging, endoscopic examination, and PET/CT scan. On day 14 of the first cycle, a second PET/CT scan was performed. Patients with no early increase in regional lymph node maximum 18F-FDG standard uptake value (SUV), detected using 18F-FDG PET/CT after first IC had better progression-free survival (hazard ratio (HR) = 0.18, 95%, confidence interval (CI) 0.056–0.585; p = 0.004) and overall survival (HR = 0.14, 95% CI 0.040–0.498; p = 0.002), and were considered responders. In this subgroup, patients who achieved a reduction of ≥ 45% maximum primary tumor SUV experienced improved progression-free (HR = 0.23, 95% CI 0.062–0.854; p = 0.028) and overall (HR = 0.11, 95% CI 0.013–0.96; p = 0.046) survival. Conclusions: These results suggest a potential role for early response evaluation with PET/CT examination in patients with LASCCHN undergoing IC. Increased regional lymph node maximum SUV and insufficient decrease in primary tumor uptake predict poorer outcomes. [ABSTRACT FROM AUTHOR]