Background: Optimal timing, either concurrent or sequential, of anti-programmed death (PD)-1 antibody with chemoradiotherapy (CRT) for LA SCCHN is unknown. Recently, JAVELIN-100 showed no benefit of adding concurrent avelumab to CRT. Methods: In this randomized, phase 2 study, patients (pts) with intermediate risk human papillomavirus (HPV) positive oropharyngeal ( > 10 pack years or T4 or N3) or HPV negative previously-untreated LA SCCHN of the oropharynx, hypopharynx, larynx, or oral cavity (unselected PD-L1 status) were randomized 1:1 (stratified by HPV and nodal stage) to receive CRT (cisplatin 40 mg/m² weekly + radiation therapy consisting of 70 Gy in 35 fractions and concurrent or sequential pembrolizumab (pembro) 200 mg q 3 week X 8 doses total. Pembro was started 1 week prior to CRT and 2 weeks after CRT in the concurrent and sequential arms respectively. The primary objective was to evaluate two schedules of pembro (concurrent vs. sequential) combined with CRT in order to recommend the regimen to be tested subsequently. The study was powered to detect a signal of antagonism, defined as a 1-year local failure rate exceeding 60% and each arm had to meet all of the following: dose limiting toxicity (DLT) rate £ 20%, 1-year local failure rate (LRF) < 60%, and 1-year PFS ³ 60%. If all three were met the arm with a numerically superior 1-year PFS would be selected for further study. Extensive correlatives were collected and will be reported in the future. Results: Between 05/2016 and 05/2021, 80 patients were randomized, 41 participants received concurrent while 39 patients received sequential pembro along with CRT. Minimum follow-up is 9 months with a median > 24 months. Both treatment schedules met the predefined composite endpoints of rate of DLT, LRF, and 1-year PFS. The 1 and 2-year PFS for sequential pembro of 89% was numerically higher than that of 82% and 78% for concurrent pembro. OS at 1 and 2 years was 94% for sequential and 82% and 78% for concurrent pembro. Median PFS and OS was not reached in either arm. 3-year PFS and OS will be reported along with PD-L1 status and other exploratory correlatives. Grade 3 adverse events were 76.7% with concurrent vs 58.9% with sequential pembro added to CRT. There were 2 Grade 5 events with sequential and 3 Grade 5 with concurrent pembro. Conclusions: This randomized phase II trial evaluated fixed-dose concurrent versus sequential pembro added to standard CRT in LA SCCHN. Sequential pembro had a numerically superior 1 and 2-year PFS compared to concurrent therapy. Sequential pembro is the preferred regimen to compare with standard of care CRT for LA SCCHN in a phase III trial. Clinical trial information: NCT02777385.