Purpose-We have previously reported that metabolic tumor volume (MTV) obtained from pretreatment FDG PET/CT predicted outcome in patients with head-and-neck cancer (HNC). The purpose of this study is to validate these results on an independent dataset, determine if the primary tumor or nodal MTV drives this correlation, and explore the interaction with p16 INK4a status as a surrogate marker for HPV.Methods and Materials-The validation dataset in this study included 83 patients with squamous cell HNC who had a FDG PET/CT scan prior to definitive radiotherapy. MTV and SUV max were calculated for the primary tumor, involved nodes, and the combination of both. The primary endpoint was to validate that MTV predicted progression-free survival and overall survival. Secondary analyses included determining the prognostic utility of primary tumor versus nodal MTV.Results-Similar to our prior findings, an increase in total MTV of 17 cm 3 (difference between 75 th and 25 th percentile) was associated with a 2.1 fold increase in the risk of disease progression (p=0.0002), and a 2.0 fold increase in the risk of death (p=0.0048). SUV max was not associated with either outcome. Primary tumor MTV predicted progression-free (HR=1.94; p<0.0001) and overall (HR=1.57; p<0.0001) survival, whereas nodal MTV did not. In addition, MTV predicted progression-free (HR=4.23; p<0.0001) and overall (HR=3.21; p=0.0029) survival in patients with p16 INK4a positive oropharyngeal cancer.Conclusions-This study validates our previous findings that MTV independently predicts outcomes in HNC. MTV should be considered as a potential risk stratifying biomarker in future studies of HNC.