Background: Immune checkpoint inhibitors (ICI) are the standard of care in recurrent/metastatic SCCHN but their role in the curative therapy setting with RT is under study. We evaluated the novel approach of combining Nivo, a PD-1 inhibitor, and Ipi, a CTLA-4 inhibitor, in lieu of chemotherapy, with concurrent RT in pts with high-risk LA SCCHN. Methods: We enrolled newly diagnosed, chemotherapy eligible pts with AJCC 7^th edition stage IVA-IVB SCCHN of the oral cavity, oropharynx (OP), hypopharynx, and larynx. HPV+ OP were T4, N2c or N3 OP. Nivo (3 mg/kg every 2 weeks IV x 17 doses) and Ipi (1 mg/kg every 6 weeks x 6 doses) were administered starting 2 weeks prior to the start of RT. RT was prescribed to a dose of 70 Gy delivered in 2 Gy/fraction/day using VMAT. The primary objective was safety of combination ICI with RT. Secondary objectives included 1-year progression-free survival (PFS), overall survival, and correlative studies. Results: 24 pts were enrolled; median age of 60 (range 48-77); 20 were male; 16 oropharynx (14 HPV+), 2 hypopharynx, and 6 larynx; AJCC 7^th edition stage IVA (23), IVB (1). Grade 3 acute in-field adverse events (AEs) occurred in 17/24 (71%) of patients during concurrent ICI-RT (9 mucositis, 6 dysphagia, 5 dermatitis, 4 odynophagia, 1 dysphonia); there were no grade 4/5 AEs during ICI-RT. During ICI maintenance 5 pts developed in-field ulcerations at the primary site detected at an average of 3 months post RT; 1 of them died of bleeding due to erosion into the carotid artery with no evidence of active cancer; 4 additional pts developed in-field necrosis. 7 pts discontinued ICI treatment at > 3 months post-RT: 1 due to immune AE, 5 due to in-field ulcerations, 1 due to persistent mucositis without ulceration. 4 pts (17%) had grade 3 immune AEs: 1 elevation of lipase, 1 colitis, and 2 rash. There were no grade 4/5 immune AEs. The median follow-up is 16 months (range, 6.3-30.6). 21 of 24 pts (87.5%) are alive with no evidence of disease progression. 2 pts recurred at distant sites: 1 had a solitary lung lesion at 11 months and was treated with RT; 1 in mediastinal lymph nodes at 9 months and was treated with chemo-RT. Locoregional control remains at 100%. Conclusions: RT plus dual ICI combination was feasible and resulted in no locoregional relapses so far in 24 high-risk LA SCCHN pts. Longer follow-up is needed to fully assess PFS and locoregional control as well as post-treatment in-field ulceration/necrosis that may be attributed to the potent radiosensitizing effect of dual PD-1 and CTLA-4 blockade. Clinical trial information: NCT03162731.