Background: We here-in report 2 year cancer control outcomes from a prospective phase II clinical trial evaluating de-intensified chemoradiotherapy (CRT) for patients with favorable risk, HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods: The major inclusion criteria were: T0-T3, N0-N2c, M0, HPV or p16 positive, and minimal smoking history. Treatment was limited to 60 Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatin (30 mg/m²). Patients neither received induction chemotherapy nor definitive surgery. The primary study endpoint was pathologic complete response rate (pCR) based on required biopsy of the primary site and dissection of pretreatment positive lymph node regions, regardless of radiographic response. Secondary endpoint measures included 2 year local control (LC), regional control (RC), cause specific survival (CSS), distant metastasis free survival (DMFS), and overall survival (OS), and patient reported symptoms (PRO-CTCAE) and quality of life (EORTC QLQ-C30 & H&N35). Results: Forty-four patients enrolled and the median f/u was 36 months (range 5-53 months, 93% with > / = 1 year, 88% > / = 2 years). We have previously reported the pCR to be ~ 86%. Two year LC, RC, CSS, DMFS, and OS are the following: 100%, 100%, 100%, 100%, and 95%. All 6 patients who had pathological partial responses are alive with no evidence of disease with a median f/u of 34 months (range 9-48 months). Two patients have died (stroke and glioblastoma). Mean pre and 2-year post EORTC QOL scores were: Global 80/82 (lower worse), Swallowing 11/10 (higher worse), Dry Mouth 16/54, and Sticky Saliva 6/33. 39% of patients required a feeding tube (none permanent) for a median of 15 weeks (5 - 22 weeks). Mean pre and 2 year post PRO-CTCAE (1 to 4 scale, higher worse) scores were: Swallowing 0.4/0.8 and Dry mouth 0.4/1.8. There were no > / = Grade 3 late adverse events. Conclusions: The 2-year clinical outcomes with decreased intensity of therapy with 60 Gy of IMRT and weekly low-dose cisplatin are excellent in favorable risk OPSCC with evidence of better preservation of quality of life as compared to standard therapies. Clinical trial information: NCT01530997.