Background: Human Papilloma Virus (HPV)-driven head and neck cancer (HNSCC) is associated with good prognosis. The prognostic value of HPV-DNA and p16 IHC was recently reported by this consortium. Discordance between HPV and p16 status is consistently observed impacting patient stratification and treatment outcome. We sought to overcome this limitation by developing a next-generation methylome-based classifier of HPV-driven HNSCC. Methods: HPV-DNA and p16 status of a DKTK-ROG multicenter retrospective cohort of patients (n = 194) with oropharynx cancer (OPC), oral cavity- and hypopharynx cancer (non-OPC), homogenously treated with surgery and adjuvant cisplatin-based radiochemotherapy (RCHT), was employed as a training set. Five validation cohorts were utilized including DKTK-ROG patients with definitive RCHT (n = 110), three additional RCHT cohorts from Heidelberg, Dresden, Munich (n = 222) and The Cancer Genome Atlas – HNSCC cohort (TCGA, n = 206). Overall methylome data from 732 samples including two different sources (FFPE/FrFr) and platforms (Illumina 450K and EPIC 850K) were studied. Results: A 24-probe set methylome-based classifier of HPV-driven HNSCC was discovered (HPV-M) to significantly correlate with improved clinical outcomes: HR for local recurrence (range 0.11-0.19), disease progression (range 0.16-0.29) and overall survival (OS, range 0.19-0.42) were significant in all cohorts (p < 0.05). Notably, HPV-M+ classification was superior to HPV-DNA+ status or p16+ IHC in predicting OS in all cohorts independent of tumor localization (OPC/non-OPC). Likewise, HPV-M showed a strong correlation with HPV-DNA and p16 status (p < 0.0001). Across cohorts ~ 10% discordance between HPV-M and HPV-DNA or p16 status was found, respectively. Among these patients (n = 71), OS was significantly reduced in patients with HPV-M negative vs. positive tumors (p < 0.009). Conclusions: We present a novel robust and independent methylome-based classifier of HPV-driven HNSCC that could be instrumental for accurate patient stratification in the era of de-escalation trials.