Purpose In the context of oropharyngeal cancer treated with definitive radiotherapy, the aim of this retrospective study was to identify the best threshold value to compute metabolic tumor volume (MTV) and/or total lesion glycolysis to predict local-regional control (LRC) and disease-free survival. Methods One hundred twenty patients with a locally advanced oropharyngeal cancer from 2 different institutions treated with definitive radiotherapy underwent FDG PET/CT before treatment. Various MTVs and total lesion glycolysis were defined based on 2 segmentation methods: (i) an absolute threshold of SUV (0-20 g/mL) or (ii) a relative threshold for SUVmax (0%-100%). The parameters' predictive capabilities for disease-free survival and LRC were assessed using the Harrell C-index and Cox regression model. Results Relative thresholds between 40% and 68% and absolute threshold between 5.5 and 7 had a similar predictive value for LRC (C-index = 0.65 and 0.64, respectively). Metabolic tumor volume had a higher predictive value than gross tumor volume (C-index = 0.61) and SUVmax (C-index = 0.54). Metabolic tumor volume computed with a relative threshold of 51% of SUVmax was the best predictor of disease-free survival (hazard ratio, 1.23 [per 10 mL], P = 0.009) and LRC (hazard ratio: 1.22 [per 10 mL], P = 0.02). Conclusions The use of different thresholds within a reasonable range (between 5.5 and 7 for an absolute threshold and between 40% and 68% for a relative threshold) seems to have no major impact on the predictive value of MTV. This parameter may be used to identify patient with a high risk of recurrence and who may benefit from treatment intensification.