Background: The rapid increase in oropharyngeal squamous cell carcinoma (OPSCC) incidence in the developed world has been attributed to a rise in Human Papillomavirus (HPV) infection. HPV related OPSCC is considered a distinct disease entity affecting a younger and healthier patient population. As such, acute and late toxicities, and the subsequent treatment strategy of those toxicities, have a significant impact on healthcare systems and societies, as well as patient lives. Standard platin-based chemoradiotherapy is associated with considerable acute toxicity and long term sequelae. De-ESCALaTE is a pragmatic, multi-centre, open label randomised clinical trial addressing the need to establish less toxic therapy in low-risk HPV positive head and neck cancer. Methods: Patients with low-risk HPV+ OPSCC are randomised to receive radiotherapy (70G in 35F) and either cisplatin (100 mg/m² x 3) or cetuximab (400 mg/m² loading dose followed by weekly 250 mg/m²) and will be followed up for two years. Patients who have a significant smoking history (i.e. more than 10 pack years) and advanced nodal status (i.e. N2b, N2c or N3) are excluded from this trial. The primary outcome measure is the total number of acute (occurring during treatment or up to 90 days after treatment) and late (occurring between 90 days and two years after treatment) severe or life threatening (Grades 3-5) events, which has been chosen because these events result in significant morbidity and a reduction would be considered beneficial by both patients and clinicians. The sample size calculation is based on the total number of toxicity events rather than the number of patients affected. This ensures that the risk of underestimation of the toxicity burden is minimised. Secondary outcomes are overall survival, quality of life and feeding tube use. Current enrolment into the De-ESCALaTE trial [ISRCTN number: ISRCTN33522080] is 239 randomised patients with a target total of 304 patients. The IDSMC last reviewed the trial in May 2015 and suggested that the trial continue as planned. Clinical trial information: ISRCTN33522080.