Background: Plasma circulating tumor modified viral human papillomavirus (HPV) DNA (TTMV) is a sensitive and specific biomarker of HPV+ oropharyngeal squamous cell carcinoma (HPVOPC). Patients with unresectable locally advanced (LA) HPVOPC are currently treated with induction chemotherapy (IC) and standard (sd) or reduced dose (rd) of chemoradiation (CRT). Post IC TTMV can be used in the future to help assign patients to sdCRT or rdCRT. This approach may help to maintain high efficacy and minimize long-term side effects of CRT in HPVOPC. Methods: Patients with LA HPVOPC and High Risk (HR) features (radiographic ECE, T4 primary, >N2c, and isolated lung metastases) were treated with 3 cycles of TPF IC followed by rdCRT to 5600 cGy with weekly carboplatin in responders, sdCRT in clinical non-responders and in M1 patients who also received SBRT to isolated biopsy proven lung metastases. Patients with > 20 pack year smoking history were excluded. Patients were eligible for rdCRT if they had a significant clinical response to IC and were participating in the QB2 trial (NCT02945631). Results: Fourteen subjects had pre and post IC TTMV testing available for analysis. 9/14 subjects after IC received rdCRT to 5600 cGy with weekly Carboplatin. 2 subjects were removed from the QB study for clinically inadequate response, 1 withdrew consent and 2 were M1 and treated for cure. All 5 underwent sdCRT 7000 cGy. 13/14 patients had TTMV testing done prior IC, 1 subject had TTMV done after the start of cycle 1 of IC; all 14 of them had a pretherapy or (1 subject) immediate post infusion positive elevated TTMV test. 11/14 subjects developed negative TTMV after 1 or 2 cycles IC. 3/14 subjects after 1 cycle and additional 6/14 subjects after 2 cycles of IC developed negative TTMV. 3/14 subjects still had abnormal TTMV after 3 cycles of IC; 2/3 subjects underwent 7000 cGy. Remaining 1/3 had a negative repeat TTMV prior to CRT and underwent rdCRT with 5600 cGy. TTMV testing was done for all subjects after completion CRT and all were negative. All subjects in addition to standard surveillance had TTMV testing done during their surveillance visits. 2 subjects developed recurrent HPVOPC after CRT: 1 locoregional and 1 metastatic (elevated TTMV after IC; sdCRT). Conclusions: In contrast to NCCN guidelines, rdCRT in many academic institutions has become a standard for HPVOPC. We have demonstrated a prompt reduction of TTMV to 0 in a subset of patients receiving 1 cycle and in a majority after at least 2 cycles of IC. The small sample size of our study lacks the statistical power to demonstrate that the failing to attain negative TTMV after/during IC is associated with a poor prognosis and warrants more aggressive therapy. TTMV biomarker response may have important prognostic value in delivering primary therapy and warrants further larger and more structured studies.