Background: TORS has improved the likelihood of identifying an oropharyngeal cancer for patients presenting with unknown primary. We evaluate the oncologic and functional outcomes after reduction of RT volumes based on TORS findings. Methods: Patients with p16-positive, neck SCC (cN1-N3) with no primary on examination and CT/MRI were included between 08/2017 and 12/2019. All patients underwent PET-CT, surgical evaluation with either therapeutic intent including neck dissection for cN1 without extranodal extension (Group 1, n=9) or diagnostic intent (Group 2, n=13). Patients underwent excision of palatine tonsil (PT) followed by lingual tonsil (LT), if the PT was negative, or excision of PET-CT avid regions. Pharyngeal-sparing radiotherapy (PSRT) was given when no primary was found (pT0) and for primaries completely excised (margins >= 3mm). Unilateral neck radiotherapy (UNRT) was given for lateralized (>1 cm from midline) primaries or pT0 with unilateral disease. The primary outcome was 2-year out-of-treated volume failures (OTVF). Swallowing-related quality of life (SR-QOL) was measured using MD Anderson Dysphagia Inventory (MDADI) composite score. A sample size of 22 was required assuming OTVF cannot exceed 15% (vs. 1% historical), power of 0.8, alpha of 0.05 (one-sided), and loss to follow-up of 10%. Results: All 22 patients [median age 60 (46-68); 86% male; 86% N1, 9% N2, 5% N3] underwent surgical evaluation. PET-CT showed suspicious findings in 12 (55%) [sensitivity = 0.44, specificity = 0.29]. Excision of PT and LT were performed in 14 (64%) and 14 (64%) patients respectively; and 8 (36%) had previous PT. Oropharyngeal primaries were found in 17 patients (77%) [14 (64%) single primary, 3 (13%) two primaries]. RT volume de-intensification was achieved in 11 patients (50%) who had PSRT and 10 (45%) who had UNRT. In Group 1, adjuvant RT was given to 6 (67%) and CRT to 1 (11%). In group 2, 8 (62%) had RT and 5 (38%) had CRT. There were no OTVF, local, or regional failures [median follow-up 29 months]. Two-year OS, DFS, and LRC were 100%, 95%, and 100%. SR-QOL showed good recovery (Table). Grade III/IV surgical as well as acute and late toxicities occurred in 2 (9%), 5 (23%), and 1 (5%) respectively. Conclusions: TORS evaluation for p16-positive unknown primary SCC allowed RT volume de-intensification with excellent disease control and quality of life. Future randomized trials can compare transoral surgery versus existing diagnostic approaches. MDADI composite scores. Clinical trial information: NCT03281499.