Purpose/Objective(s) Despite generally favorable outcomes, up to 20% of patients with human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) will experience recurrence within 5 years of curative-intent therapy; approximately half of recurrences present with distant disease. Current post-treatment surveillance practices rely on physical exams and imaging. We assessed a circulating cell-free tumor tissue modified HPV DNA (TTMV-HPV DNA) test ordered during routine clinical practice for the post-treatment surveillance of a large population of previously treated OPSCC patients with HPV-driven disease. Materials/Methods This central IRB-approved retrospective clinical case series included 1076 consecutive patients across 124 U.S. sites who were > 3 months post therapy for HPV-driven OPSCC and who had one or more TTMV-HPV DNA tests between 2/6/2020 and 6/11/2021. TTMV-HPV DNA for HPV subtypes 16, 18, 31, 33, and 35 was analyzed with ultrasensitive digital droplet PCR. Test results were compared to the results of subsequent clinical evidence of OPSCC, using nasopharyngolaryngoscopy and/or radiologic (CT, MRI, or PET-CT) evaluations and/or tissue biopsy. Results Circulating TTMV-HPV DNA was positive in 80/1076 patients (7.4%, TTMV range: 7 - 123,148 fragments (frgs)/mL) tested after definitive therapy. At the first positive surveillance test, 21/80 (26.2%) patients had known recurrence while 59/80 (73.8%) had no other evidence of disease (NED) or indeterminate disease status. Clinical follow-up was available on all patients. Among the 59 positive tests without clinically known recurrence, 55 (93.2%, TTMV range: 8 - 23,296 frgs/mL) had confirmed recurrence identified with 52 HPV 16-driven, and 1 and 2 with HPV 31 or 35-driven OPSCC respectively. Two patients have clinically suspicious lesions with negative biopsies, one with a base of tongue ulcer and one with a pulmonary nodule (TTMV range: 9-67 frgs/mL) and 2 are currently clinically NED (TTMV range: 16-79 frgs/mL) with scheduled repeat TTMV and radiologic surveillance. Conclusion These findings demonstrate the clinical validity and utility of circulating TTMV-HPV DNA testing in daily clinical practice as an effective surveillance tool for identifying patients with active and occult recurrent HPV-driven OPSCC. To date the positive predictive value for recurrence or persistence of HPV-driven OPSCC is 95.0% (76/80), which may increase with additional follow-up of cases remaining in active surveillance. Notably, the presence of circulating TTMV-HPV DNA was the first indication of recurrence for 72.4% of cases. These data will help inform clinical and guideline-endorsed strategies concerning the inclusion of circulating TTMV HPV-DNA as a biomarker of molecularly detectable HPV-driven OPSCC in the setting of recurrence surveillance. Despite generally favorable outcomes, up to 20% of patients with human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) will experience recurrence within 5 years of curative-intent therapy; approximately half of recurrences present with distant disease. Current post-treatment surveillance practices rely on physical exams and imaging. We assessed a circulating cell-free tumor tissue modified HPV DNA (TTMV-HPV DNA) test ordered during routine clinical practice for the post-treatment surveillance of a large population of previously treated OPSCC patients with HPV-driven disease. This central IRB-approved retrospective clinical case series included 1076 consecutive patients across 124 U.S. sites who were > 3 months post therapy for HPV-driven OPSCC and who had one or more TTMV-HPV DNA tests between 2/6/2020 and 6/11/2021. TTMV-HPV DNA for HPV subtypes 16, 18, 31, 33, and 35 was analyzed with ultrasensitive digital droplet PCR. Test results were compared to the results of subsequent clinical evidence of OPSCC, using nasopharyngolaryngoscopy and/or radiologic (CT, MRI, or PET-CT) evaluations and/or tissue biopsy. Circulating TTMV-HPV DNA was positive in 80/1076 patients (7.4%, TTMV range: 7 - 123,148 fragments (frgs)/mL) tested after definitive therapy. At the first positive surveillance test, 21/80 (26.2%) patients had known recurrence while 59/80 (73.8%) had no other evidence of disease (NED) or indeterminate disease status. Clinical follow-up was available on all patients. Among the 59 positive tests without clinically known recurrence, 55 (93.2%, TTMV range: 8 - 23,296 frgs/mL) had confirmed recurrence identified with 52 HPV 16-driven, and 1 and 2 with HPV 31 or 35-driven OPSCC respectively. Two patients have clinically suspicious lesions with negative biopsies, one with a base of tongue ulcer and one with a pulmonary nodule (TTMV range: 9-67 frgs/mL) and 2 are currently clinically NED (TTMV range: 16-79 frgs/mL) with scheduled repeat TTMV and radiologic surveillance. These findings demonstrate the clinical validity and utility of circulating TTMV-HPV DNA testing in daily clinical practice as an effective surveillance tool for identifying patients with active and occult recurrent HPV-driven OPSCC. To date the positive predictive value for recurrence or persistence of HPV-driven OPSCC is 95.0% (76/80), which may increase with additional follow-up of cases remaining in active surveillance. Notably, the presence of circulating TTMV-HPV DNA was the first indication of recurrence for 72.4% of cases. These data will help inform clinical and guideline-endorsed strategies concerning the inclusion of circulating TTMV HPV-DNA as a biomarker of molecularly detectable HPV-driven OPSCC in the setting of recurrence surveillance.