Purpose <p> This study systematically reviewed and conducted a meta-analysis to compare efficacy and safety of immunotherapy strategies in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), assessing PD-L1 and treatment line impact. </p> Methods <p> Eleven phase III trials (n=6045) compared three immunotherapy strategies—immune monotherapy, combination with chemotherapy/targeted therapy, or double-agent immunotherapy—against standard of care (SOC) or alternative regimen. Primary endpoints: OS (overall survival) and PFS (progression-free survival); secondary: ORR (objective response rate), grade ≥3 TRAEs (treatment-related adverse events) and treatment-related deaths. </p> Results <p> Immunotherapy plus chemotherapy/targeted improved OS (HR=0.71, 95% CI: 0.62-0.81; p&lt;0.001) and ORR (RR=1.11, 95% CI: 1.03-1.20; p=0.007) in first-line setting, with PFS benefit disappearing after trim-and-fill correction (adjusted HR=0.88, 95% CI: 0.61-1.27). Immune monotherapy enhanced OS only in second-line settings (HR=0.79, 95% CI: 0.69-0.91; p=0.001), particularly for PD-L1-positive patients (HR=0.71, 95% CI: 0.62-0.81; p&lt;0.001), while increasing mortality risk in PD-L1-negative subgroups (HR=1.40, 95% CI: 1.01-1.94; p=0.045). Double-agent immunotherapy showed no OS improvement (HR=1.01, 95%CI: 0.90-1.12; P=0.9198) and potential PFS detriment (HR=1.40, 95%CI: 0.99-1.99; P=0.059). Safety analyses indicated reduced TRAEs with monotherapy (RR=0.32) and double-agent therapy (RR=0.48), but comparable toxicity for immunotherapy plus chemotherapy/targeted therapy versus SOC (RR=1.02). </p> Conclusion <p> Current evidence supports​ immunotherapy plus chemotherapy/targeted ​as a standard first-line option​ for R/M HNSCC. Immune monotherapy is recommended for second-line PD-L1-positive patients. Available data do not support the use of​ double-agent immunotherapy. Prioritize OS over PFS in clinical decisions, and implement double-blind trials to minimize bias. </p>