Despite adjuvant (chemo)radiotherapy, patients with resected, locally advanced head and neck squamous cell carcinoma (HNSCC) have a one-year DFS of 65%–69%. The use of neoadjuvant PD-1 immune-checkpoint blockade (ICB) has shown clinical efficacy, but biomarkers of response and effectiveness on survival remain to be defined. Patients with resectable squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or oropharynx (p16-negative) at clinical stage T3-T4 and/or two or more nodal metastases or clinical extracapsular nodal extension (ENE) were eligible. Patients were randomized to receive neoadjuvant pembrolizumab 200 mg 1–3 weeks before surgery and were stratified by the presence (intermediate-risk) or absence (low-risk) of positive margins and/or ENE. They also received adjuvant radiation therapy (60–66 Gy) and concurrent. Patients with high-risk HNSCC were treated with once-weekly, concurrent cisplatin (40 mg/m2) daily. The primary endpoint was a one-year DFS. One-year overall survival (OS) and pathologic response (PR) were the secondary outcomes. Safety was calculated with CTCAE v5.0.From February 2016 to October 2020, 92 patients enrolled. The median age was 59 years (range, 27–80), 30% were female, 86% had stage T3–T4, and 69% had ≥N2. At a median follow-up of 28 months, one-year DFS was 97% (95% CI, 71%–90%) in the intermediate-risk group and 66% (95% CI, 55%–84%) in the high-risk group. Patients with a PR had significantly improved one-year DFS relative to patients without response (93% vs. 72%, hazard ratio 0.29; 95% CI, 11%–77%). There were no new safety signals discovered. In intermediate-risk HNSCC, pembrolizumab as a neoadjuvant and adjuvant increased the one-year DFS rate relative to historical control. The ICB to neoadjuvant PORT rate (dose-response curve) is a potential surrogate for DFS.