After curative radiotherapy (RT) or chemoradiation (CRT), there is no validated tool to accurately identify patients for adjuvant therapy in nasopharyngeal carcinoma (NPC). Post-radiotherapy circulating plasma Epstein-Barr virus (EBV) DNA can detect minimal residual disease and is associated with recurrence and survival independent of TNM stage. We aimed to develop and validate a risk model for stratification of NPC patients after completion of RT/CRT to observation or adjuvant therapy.The prospective multi-center 0502 EBV DNA screening cohort enrolled from 2006-2015 (n=745) was used for model development. For internal validation, we pooled independent patient cohorts from prospective clinical studies enrolled from 1997-2006 (n=340). For external validation, we used retrospective cohort of NPC patients treated at Sun Yat-sen University Cancer Center from 2009-2012 (n=837). Eligible patients had histologically confirmed NPC of UICC 7th Edition stage II-IVB who completed curative RT/CRT with or without neoadjuvant chemotherapy, had post-radiotherapy EBV DNA tested within 120 days after RT, and received no adjuvant therapy. The primary endpoint was overall survival (OS). We used recursive-partitioning analysis (RPA) to classify patients into groups of low-, intermediate- and high-risk of death.Combining post-radiotherapy EBV DNA level (0, 1-49, 50-499, >=500 copies/ml) and TNM stage (II, III, IVAB), RPA model classified patients into low-, intermediate- and high-risk groups with 5-year OS of 89.4%, 78.5% and 37.2% respectively. The RPA low-risk group had comparable OS to TNM stage II (5-year OS 88.5%) but identified more patients (64.8% versus stage II 28.1%) that could potentially be spared adjuvant therapy toxicity. RPA model (c-index 0.712) showed better risk discrimination than either TNM stage (0.604) or post-RT EBV DNA alone (0.675) with improved calibration and consistence. These results were validated in both internal and external cohorts.Combining post-radiotherapy EBV DNA and TNM stage improved risk stratification in NPC.