Background: Pembrolizumab, an anti-PD1 monoclonal antibody, improves survival in advanced HNSCC. Patients with pathologic high risk, HPV-negative HNSCC have a high recurrence rate despite adjuvant cisplatin-IMRT (CRT), the current standard. Immunosuppression is induced by HNSCC and CRT, and may be reversible by targeting PD1. Methods: We conducted a phase I trial with expansion cohort to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to adjuvant CRT (NCT02775812). Eligibility: oral cavity, pharynx, or larynx primary; HPV-negative; pathologic high risk (positive margin or extranodal extension [ENE]); Zubrod 0-1. During phase I, patients enrolled in descending cohorts of 12 (Table). RP2S was declared if ≤ 3 dose-limiting toxicities (DLT) occurred. DLT was defined as ≥ Grade 3 non-hematologic adverse event (AE) related to pembrolizumab, immune-related (ir)AE requiring > 2 weeks of systemic steroids, or unacceptable delay in IMRT. The expansion cohort enrolled 20. Results: From Nov 2016-Oct 2018, 34 eligible patients enrolled at 22 NRG institutions. During the first cohort, 1 DLT was observed (Grade 3 fever). RP2S was declared as Schedule 3 and the expansion cohort triggered. Among all 34 patients, median age was 60 years (26-83); 68% were male; 74% had Zubrod 1; 85% had oral cavity; 88% had ENE; 21% had positive margin. During expansion, 3 additional patients with DLT were observed: wound infection; diverticulitis; nausea. No DLT unacceptably delayed IMRT. Twenty-eight of 34 (82%) received ≥ 5 doses of pembrolizumab; 17 (50%) got all 8 doses. Thirty-one of 32 (97%) DLT-evaluable patients received all adjuvant RT; 1 withdrew consent after starting protocol. Conclusions: The RP2S is pembrolizumab 200 mg IV q 3 weeks for 8 doses, starting the week before adjuvant CRT. This regimen was safe and feasible in a cooperative group setting. irAE were rare in this population. Clinical trial information: NCT02775812