Background: Locally advanced Human Papillomavirus (HPV) + oropharyngeal carcinoma (OPC) has a significantly better response, locoregional control and survival compared to non HPVOPC. Standard-dose chemoradiotherapy (sdCRT) results in significant side effects, leading to acute and life-threatening late morbidity. We studied whether reduced dose chemoradiation (rdCRT) after induction chemotherapy (IC) resulted in equivalent progression-free survival (PFS) compared to sdCRT + IC with decreased late morbidity. Methods: Patients with locally advanced OPC and < 20 pack years (py) smoking history were tested for p16 and then HPV by type-specific PCR. After 3 cycles of docetaxel, cisplatin and fluorouracil (TPF) IC all HPV+/p16+ subjects underwent clinical and radiographic evaluation. Clinical responders were randomized to either sdCRT (70Gy) or rdCRT (56Gy) with weekly carboplatin (AUC 1.5) at a 1:2 ratio. The primary endpoint was 2 year PFS; the secondary endpoint was 2 year overall survival (OS). Toxicity, late morbidity and swallowing were monitored. Results: 23 patients were enrolled and 20 randomized, 8 to sdCRT and 12 to rdCRT; 2 were HPV- and 1 refused further therapy after IC and were not randomized. Median age was 56.5 yrs (range 36-78); 30% were African-American, 10% were Hispanic, 5% were female; 16 were HPV 16+ and 4 were other high risk (HR) variants; 60% never smoked, 25% were < 10 py, and 15% were 10-20 py; 70% had high risk features: T4, N2c, or N3. Clinical response to TPF was 100%; 70% had a clinical complete response. As of February 1, patients have been followed for a median of 37.5 months (range 21.7 – 49.5). 2 year PFS/OS for sdCRT and rdCRT are 87.5% vs 83.3% (log-rank test p = 0.85), respectively. All 3 failures were local or regional and 2 of 3 occurred in non HPV16 HR variants. Conclusions: HPV+ OPC patients who received rdCRT after TPF IC had similar PFS/OS compared to those receiving sdCRT. These results uphold the potential clinical benefit of radiation dose reduction as a treatment option with comparable survival to the standard radiation dose. A Phase III trial comparing IC plus rdCRT to sdCRT alone or with IC is warranted in this population. Non-HPV16 HR variants may have a worse outcome. Clinical trial information: NCT01706939