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Human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is the fastest rising cancer in North America, with generally favourable prognosis. There is significant interest in treatment de-escalation for these patients, but 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to predict survival of patients with newly diagnosed HPV+ HNSCC. We created an RNA-based prognostic score which was successfully validated in six cohorts comprising a total of 906 patients, including blinded external validations in a large retrospective cohort (n = 269) and in a prospective cohort (BD2Decide, NCT02832102, n = 286). We assessed the feasibility of using IHC to calculate the UWO3 score using an immunohistochemistry-based tissue microarray cohort (n = 197). Transcriptomic data from two aggressive treatment de-escalation cohorts were used to assess ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 score and outcomes, adjusting for potential confounders. Analysis of HPV+ HNSCC tumours revealed three distinct tumor microenvironment subtypes: immune rich, immune desert, and mixed. A three gene immune score (UWO3) classified patients into the three immune groups and was strongly associated with disease-free survival in six datasets, including blinded validation in a retrospective and a prospective dataset. Pooled analysis (n = 906) demonstrated that the immune rich group had superior disease-free survival at 5 years. The association between UWO3 immune class and time to recurrence was independent of patient age, sex, smoking status, alcohol intake status, and AJCC 8th edition clinical stage. Finally, UWO3 was able to identify patients who respond to aggressive treatment de-escalation to 30 Gy radiation in two treatment de-escalation cohorts. The UWO3 immune score could inform clinical decision making for patients with HPV+ HNSCC based on robust outcome prediction across six independent cohorts. The superior survival of immune rich patients supports de-intensification strategies for this cohort, while the inferior outcomes of the immune desert patients suggest potential for intensification and/or immunotherapy. Prospective de-escalation and intensification clinical trials are currently being planned. [ABSTRACT FROM AUTHOR]