Purpose: Among head and neck squamous cell carcinomas (HNSCCs), oropharyngeal cancer (OPC) was historically thought to be a homogenous entity, mainly caused by excessive alcohol and tobacco consumption. However, the discovery of human papillomavirus (HPV) infection as an independent risk factor for the development of OPC has led to changes in diagnostics and treatment of this cancer. HPV-positive OPC is associated with improved survival and reduced recurrence rates compared to similar stage HPV-negative OPC and HNSCC in general. These favorable outcomes have led the medical and scientific communities to consider de-escalation treatment options in this specific population to spare patients from unnecessary toxicity, without compromising survival. This comment aimed to critically evaluate de-intensification treatment strategies in HPV-related OPC and to propose future treatment approaches as well as trial design. ----- Methods: A review of the literature was performed. ----- Results: Among nine published non-surgical de-intensification trials, only three studies had a comparison head-to-head with the standard of care, with two trials demonstrating clear inferiority of de-escalating treatment option (cetuximab-based radiotherapy). Additionally, there has been significant heterogeneity among induction chemotherapy (IC) protocols in de-escalating studies. Also, the toxicity among these studies varies in terms of the manner of reporting (physician vs patient-reported adverse events). ----- Conclusions: Data obtained with de-intensified strategies should only serve to help select an appropriate experimental arm for a randomized controlled trial phase III comparison against cisplatin and 70 Gy of radiotherapy. Without a proper randomized trial, there remains the possibility of compromising survival, which raises ethical questions about conducting any de-escalation trial.