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Purpose: To investigate the metabolic information provided by (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) during the early response of head-and-neck squamous cell carcinoma (HNSCC) xenografts to radiotherapy (RT). Methods and Materials: Low-passage HNSCC cells (UT14) were injected into the rear flanks of female nu/nu mice to generate xenografts. After tumors grew to 400-500 mm(3), they were treated with either 15 Gy in one fraction (n = 18) or sham RT (n = 12). At various time points after treatment, tumors were assessed with 2-h dynamic FDG-PET and immediately harvested for direct histological correlation. Different analytical parameters were used to process the dynamic PET data: kinetic index (Ki), standard uptake value (SUV), sensitivity factor (SF), and retention index (RI). Tumor growth was assessed using the specific growth rate (SGR) and correlated with PET parameters using the Pearson correlation coefficient (r). Receiver operating characteristic (ROC) and the area under the ROC curve (AUC) were used to test PET parameters for their ability to predict for radiation necrosis and radiation change. Results: Tumor growth was arrested for the first 20 days after RT and recovered thereafter. Histologically, radiation change was observed in the peripheral regions of tumors between days 7 and 23 after RT, and radiation necrosis were observed in the central regions of tumors between days 7 and 40. Ki provided the best correlation with SGR (r = 0.51) and was the optimal parameter to predict for early radiation necrosis (AUC = 0.804, p = 0.07). SUV(30 min) was the strongest predictor for late radiation necrosis (AUC = 0.959, p = 0.004). Both RI(30-60 min) and SF(12-70 min) were very accurate in predicting for radiation change (AUC = 0.891 and 0.875, p = 0.009 and 0.01, respectively). Conclusions: Dynamic FDG-PET analysis (such as Ki or SF) may provide informative assessment of early radiation necrosis or radiation change of HNSCC xenografts after RT. [ABSTRACT FROM AUTHOR]