Background: One method of therapy deintensification in locally advanced (LA) HPVOPC is to reduce total radiation dose during concomitant chemoradiation (CRT) in a sequential therapy plan. We prospectively assessed differences in patient reported QoL in LA HPVOPC patients receiving reduced dose CRT versus standard dose CRT in a small randomized trial. Methods: From 2012 to 2015, out of 23 patients identified with LA HPVOPC, 20 received induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) and responders were randomized to standard CRT (70 Gy, 7 weeks) or reduced CRT (56 Gy, 5.5 weeks) each with weekly carboplatin (one did not meet inclusion criteria, two withdrew consent). Five validated QoL surveys were taken at baseline, and 3, 6, 12, and 24 months post treatment: MD Anderson Dysphagia Inventory and Symptom Inventory (MDADI, MDASI), Xerostomia Questionnaire (XQ), European Organization for Research and Treatment of Cancer Questionnaire (EORTC) with head and neck module (EORTC HN). Five were excluded in QoL analysis (three had disease progression, two with insufficient surveys). 3 and 6 month results were grouped by using the score denoting a worse QoL due to lack of survey responses (five patients missing from 3 months, one patient from 6 months). Survival data was previously reported (ASCO 2017). Results: Out of 15 patients, six received standard CRT and nine received reduced CRT. No difference was noted in baseline QoL. At 3-6 month follow up, patients receiving reduced CRT had significantly less changes in QoL from their baseline in EORTC global health score and functional scale (1.85 vs -31.67, P= 0.0363; 3.51 vs -25.8, P= 0.003), MDADI (-10.44 vs -38, P= 0.0307), XQ (2.78 v 5.8, P= 0.047), EORTC HN (0.45 vs 23.37, P= 0.029), and MDASI symptom interference (-0.22 vs 4.07, P= 0.014). Change in MDASI symptom severity approached significance (0.84 vs 2.95, P= 0.051). Change in EORTC symptom scale did not show any significant difference (0.48 vs 13.95, P= 0.101). Differences in QoL disappeared at 12 and 24 month follow up. Conclusions: Reduced dose CRT in a TPF based sequential therapy program in LA HPVOPC is feasible and results in significantly quicker improvement in QoL post therapy. Clinical trial information: NCT01706939