Background: RSPT HNSCC within a previously irradiated field presents a technical challenge portending worse outcome. Anti-PD-1 therapy is an approved standard of care in the treatment of advanced HNSCC. CA209-9KY aimed to investigate the progression-free survival (PFS), tolerability, overall survival (OS) and patient reported outcomes (PRO) of nivo during and after IMRT re-irradiation. We report here the results for 51 enrolled and evaluable patients Methods: Following IRB approval at 3 participating institutions (Emory University, Cleveland Clinic, Medical College of Wisconsin), patients (pts) were enrolled if they had RSPT in a previously irradiated field (>40Gy) and met criteria for recursive partition analysis (RPA) classes I or II (Ward et al, IJROBP 2018). Salvage resection was allowed provided the presence of pos margins, ENE, pN2/3 or pT3/4 disease, multifocal PNI, or LVI. IMRT re-irradiation to a total of 60-66 Gy in 30-33 daily fractions were delivered over 6-6.5 weeks with nivo (240 mg) two weeks prior and every 2 weeks x 5 during IMRT then at 480 mg every 4 weeks up to 52 weeks. The primary endpoint was improvement in 1-yr PFS from 40% to 55% (one-sided alpha of 0.05 and an 85% power). Results: As of 1/2022, a total of 51 evaluable pts completed IMRT with nivo. Median age 62 (56-67), RPA status 1 (23, 46%), 2 (27, 54%), Males (41, 80%), ECOG performance status 0 (13, 25%) 1 (36, 71%), 2 (2, 4%); p16 pos (16, 31%), neg (9,18%), not applicable (26, 51%). With a median follow up of 12.5 mos (11.2-14.0) the 1- yr PFS was 57.8% (95% CI, 41.3-71.1%) and OS was 81.7% (95% CI, 65.2-90.9%). Among 38 pts with available flow cytometry, pts with a 1.5-fold increase in peripheral blood PD1+KI67+CD8+ T cells (baseline to weeks 2 or 4) had an OS of 19.3 mos (vs 13.3 mos) (p=0.1617). Adverse events (AEs) (CTCAE version 4.0) included fatigue(40, 78%), dermatitis (30,58%), dysphagia (28, 54%). Most frequent serious AEs were anorexia and dyspnea (2, 4% each). Treatment related >3 AEs were lymphopenia (2, 4%), colitis, diarrhea, mucositis and nausea (1, 2% each). FACT-G and FACT-H&N QOL scores remained stable and consistent across all time points (52 weeks) (Cronbach’s alpha of > 0.7) (ASTRO 21, abstract # 2738). Conclusions: CA209-9KY met its primary endpoint of 1-yr PFS; IMRT reirradiation with concurrent and adjuvant nivo is clinically effective, well tolerated and deserves further exploration in patients with RSPT HNSCC. CA209-9KY was supported by a grant from BMS. Clinical trial information: NCT03521570.