Background: Concurrent blockade of lymphocyte activation gene 3 (LAG-3) may enhance the efficacy of anti–programmed cell death-1 (PD-1) therapies. In a Phase 1, multicohort study, fianlimab (anti–LAG-3) plus cemiplimab (anti–PD-1) showed durable responses and a generally manageable safety profile in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), warranting further investigation. Methods: This multicenter, randomized, double-blind, Phase 2 study (NCT06769698) will investigate the efficacy and safety of fianlimab plus cemiplimab versus cemiplimab monotherapy as first-line treatment in patients with R/M HNSCC with positive programmed cell death-ligand 1 (PD-L1) expression. Key inclusion criteria include age ≥18 years; histologically confirmed R/M HNSCC considered incurable by local therapies; primary tumor location of oral cavity, oropharynx, larynx, or hypopharynx (oropharynx cancer must have an HPV test, positive or negative); positive PD-L1 expression (Combined Positive Score ≥1 by immunohistochemistry); measurable disease per Response Evaluation Criteria in Solid Tumors v1.1; Eastern Cooperative Oncology Group performance status ≤1; and adequate bone marrow, hepatic, and renal function. Key exclusion criteria include progressive disease within 6 months of completing curatively intended systemic therapy for locoregionally advanced HNSCC and prior systemic anticancer therapy for R/M HNSCC. Approximately 120 patients will be enrolled in 2 cohorts: HPV positive (Cohort 1, n=60) and HPV negative (Cohort 2, n=60). Participants will be randomly assigned 1:1 to receive fianlimab plus cemiplimab or cemiplimab (350 mg) plus placebo, all given by intravenous infusion every 3 weeks. The primary endpoint is objective response rate per investigator assessment. Secondary endpoints are progression-free survival, disease control rate, duration of response, safety, pharmacokinetics, and immunogenicity.