Background: The prognosis is excellent for low-risk human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC). Current standard chemoradiotherapy (CRT) regimens cure most patients but cause significant acute (mucositis) and long-term toxicities (xerostomia and dysphagia). Toxicity is primarily determined by the dose of radiotherapy and the intensity of chemotherapy. The aim of this study is to evaluate the pathological complete response (pCR) rate of low-risk HPV-associated OPSCC after de-intensified CRT. Methods: The major inclusion criteria are: 1) T0-T3, N0-N2c, M0, 2) HPV or p16 positive, and 3) </= 10 pack-years smoking history. Patients receive 60 Gy of intensity modulated radiotherapy (IMRT) with concurrent weekly intravenous cisplatinum (30 mg/m²). CT scans are obtained 4 to 8 weeks after completion of CRT to assess response. All patients have a surgical resection of any clinically apparent residual primary tumor or biopsy of the primary site if there is no evidence of residual tumor and a selective neck dissection to encompass at least those nodal level(s) that were positive pre-treatment, within 4 to 14 weeks after CRT. Longitudinal assessments of quality of life (EORTC QLQ-C30 & H&N35, NDII), patient reported outcomes (PRO-CTCAE, EAT-10), and swallowing evaluations (modified barium swallow) are obtained prior to, during, and after CRT. The primary endpoint of this study is the rate of pCR after CRT. The null hypothesis is that the pCR rate for de-intensified CRT is at least 87%, the historical rate (based on the reported 3-year local regional control rate of 87% in the RTOG 0129). Power computations were performed for N=40, with a type I error of 14.2% if the true pCR rate is 0.87. The study will be done in 3 stages with 15+15+10 patients with interim analyses at 15 and 30 patients. The trial will be stopped if the pCR rate is </= 9/15 and 21/30. The null hypothesis will be accepted if the pCR rate is >/= 33/40. Clinical trial information: NCT01530997.