Background: To report the mature results from a prospective phase II clinical trial of highly de-intensified chemoradiotherapy (CRT) for patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods: The major inclusion criteria were: 1) T0-T3, N0-N2, M0, 2) p16 positive, and 3) minimal/remote smoking history. Treatment was limited to 60 Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatin 30 mg/m²(second choice was cetuximab). Patients with T0-T2 N0-1 disease did not receive chemotherapy. All patients had a 10 to 12-week post-treatment PET/CT to determine need for planned neck dissection. The primary study endpoint was 2 year progression free survival (PFS). Secondary endpoint measures include 2 year local control (LC), regional control (RC), distant metastasis free survival (DMFS), cause specific survival (CSS) and overall survival (OS), and patient reported symptoms (PRO-CTCAE) and quality of life (EORTC QLQ-C30 & H&N35). Results: 114 patients were enrolled (median f/u of 28.8 months, range 2.6 to 51.4) with 84 having a minimum follow-up of 2 years. Smoking status was as follows: 47% never, 33% ≤ 10 pack years, and 19% > 10 pack years. Post-treatment PET/CT complete response rate was 93% at the primary site and 80% in the neck. Eleven patients had planned neck dissection with 4 having pathological residual disease. Two year LC, RC, DMFS, PFS, CSS, and OS were the following: 96%, 99%, 91%, 88%, 97%, and 95%. Neither smoking status nor receipt of cetuximab correlated with recurrence. Four patients with recurrent disease had PIK3CA mutations. Thirty four percent of patients required a feeding tube (none permanent) for a median of 10.5 weeks. Mean pre- and 2-year post-treatment EORTC QOL scores were: Global 79/83 (lower worse), Swallowing 8/9 (higher worse), Dry Mouth 14/45 (higher worse), and Sticky Saliva 9/28 (higher worse). Mean pre- and 2 year post-treatment PRO-CTCAE (0 to 4 scale, higher worse) scores were: Swallowing 0.5/0.7 and Dry mouth 0.4/1.4. There were no ≥ Grade 3 late adverse events. Conclusions: Clinical outcomes with a highly de-intensified CRT regimen of 60 Gy IMRT with concurrent low-dose cisplatin are excellent in patients with HPV-associated OPSCC. Clinical trial information: NCT02281955