<h3>Purpose/Objective(s)</h3> We previously reported the results of a phase III clinical trial (MC1675) evaluating 30-36 Gy of adjuvant radiation therapy (RT) with weekly docetaxel (DART) vs standard of care (SOC) adjuvant (chemo)RT. We analyzed prospectively collected patient plasma specimens for circulating tumor tissue modified viral (TTMV)-HPV DNA as a marker of molecular residual disease (MRD) and its association with outcomes. <h3>Materials/Methods</h3> The DART regimen consists of transoral surgery (TOS) & neck dissection for a margin negative resection. Patients (pts) with intermediate risk factors received 30 Gy/1.5 Gy b.i.d. + docetaxel 15 mg/m<sup>2</sup> days 1 & 8, while pts with extranodal extension (ENE) received a simultaneous boost to 36 Gy/1.8 Gy b.i.d. to ENE+ nodal levels. Pts randomized to SOC received 60 Gy +/- cisplatin. Pts could optionally consent to plasma collection prior to surgery, post operatively, and 3 months after completion of RT. 2mL samples were de-identified and analyzed for TTMV-HPV DNA for HPV subtypes using a commercial test in a blinded fashion. A TTMV Score of >/= 5 normalized TTMV-HPV DNA fragments (frgs)/mL plasma was prespecified as MRD. Descriptive rates are reported along with Kaplan Meier (KM) estimates for progression free survival (PFS) by traditional risk factors and TTMV-HPV DNA. KM estimates were planned for patients treated per protocol. <h3>Results</h3> Of the 194 patients (DART: 130, SOC: 64), 150 had plasma available for analysis at any timepoint. Of 44 pts with pre-surgery plasma available, 37 (84%) had detectable TTMV-HPV DNA, with a median value of 250 frgs/mL (range 5-31092). Post-op, 137 pts had plasma available (median 21 days post-op), of which 16 (11%) had detectable post op TTMV-HPV DNA, median 10 frgs/mL. Three months after completion of RT, 114 pts had plasma available, of which 8 pts (7%) had detectable TTMV-HPV DNA median 43 frgs/mL. At 18 months, PFS was 73.1% for patients with post-op detectable MRD compared to 95.8% of patients with no MRD (p<0.01). Similarly, MRD at 3 months post treatment was associated with a PFS of only 25% at 18 months compared to 97.2% PFS in patients without MRD (p<0.0001). For pts receiving DART with ENE and pN1 disease, 18-month PFS was 66.7% in the setting of MRD compared to 88.8% for no MRD (p=0.08). <h3>Conclusion</h3> This secondary analysis of MC1675 validates post-op detectable TTMV-HPV DNA as a risk factor for recurrence and demonstrates 3-month post treatment TTMV-HPV DNA as an additional highly significant MRD timepoint identifying at least 50% of all recurrences. Assay standardization is paramount to future studies as well as pre-op collection on all patients. For patients with clinical risk factors such as ENE, our data support the hypothesis that post-op TTMV-HPV DNA could aid in patient selection for de-escalation.