Incidence of human papillomavirus (HPV)-associated oropharyngeal cancer continues to increase globally. The younger age, significant better survival, and longer expected duration of life in this population have led to the popularization of the concept of treatment de-escalation. Multimodality treatment achieves a high percentage of cure in HPV+ OPC, but also brings on high rate of treatment-related morbidity. As a result, de-escalation of treatment for limiting toxicity without compromising high cure rates has emerged as a major issue in in HPV+ OPC clinical research. Primary surgery with minimally invasive excision of the primary tumor may allow for the elimination of chemotherapy and decrease radiation dose intensity. Primary dose-reduced radiotherapy, with or without systemic therapy, is also under study, as is replacing concurrent cisplatin with newer systemic agents. The recent published outcomes of the first 2 randomized de- escalation trials, however, have shown a significant worsening in survival when cisplatin is omitted or substituted. Two large phase III trials, RTOG 1016 and De-ESCALaTE, which attempted to reduce toxicity by replacing radiotherapy in combination with cisplatin with the use of cetuximab in combination with radiotherapy, recently suggested that radiotherapy + cetuximab leads to decreased survival compared with standard therapy (observed HRs of 1.45 and 5 in RTOG 1016 and De-ESCALaTE), as well as increased rates of locoregional failure. In view of these results, implementation into clinical practice before high-level evidence available should not be undertaken. Finally, harm- minimization techniques should also be evaluated as an alternative to de-escalation of treatment in these patient groups.