Aims We describe the study design and feasibility of the first Australian prospective clinical trial implementing FMISO PET-guided major RT dose de-escalation for HPV OPSCC. Methodology Patients with cT1-2N1-2b (AJCC 7th ed.) HPV OPSCC or carcinoma of unknown primary (CUP) with dual p16 and HPV positivity will be eligible. Patients will undergo surgical management of the primary (robotic surgery/negative margins not mandated) or EUA/tonsillectomy for CUP then commence RT. FMISO PET will be performed at baseline (before RT) and after two weeks of RT. Patients with absence of hypoxia at baseline or resolution of hypoxia on intra-treatment PET will undergo RT de-escalation to 30 Gy (2 Gy per fraction) concurrent with 2 cycles of high dose cisplatin at 100mg/m2, while the remainder will be treated to 70Gy (2 Gy per fraction) with 3 cycles of concurrent high dose cisplatin at 100mg/m2. De-escalated patients will undergo planned neck dissection four months after RT to assess pathologic response. 20 patients will be recruited and compared to an historical cohort to assess appropriateness of proceeding to a larger trial. Primary endpoint is pathologic response rate at neck surgery. Secondary endpoints include toxicities (CTCAE v5), quality of life (EORTC QLQC30 and HN-35), and correlation of hypoxic regions on FMISO PET with oxygen-enhanced MRI. Results The first patient was recruited in May 2025, and nine patients are currently on trial; one on follow up and eight in the active trial phase. There have been no safety events of concern. Conclusion We describe the first Australian study of FMISO PET-guided major RT dose de-escalation for HPV OPSCC, with efficacy and safety outcomes to be reported following completion of accrual in 2027 (anticipated). The results will inform the design of larger prospective trials of hypoxia-guided RT de-escalation.