OBJECTIVES: Chemoradiotherapy (CRT) or radiotherapy (RT) combined with cetuximab (for cisplatin-ineligible patients) is the standard of care (SoC) for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). This study investigates whether adding programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors (ICIs) to standard therapy improves survival in patients with LA-HNSCC. METHODS: A comprehensive search of PubMed, Embase, and the Cochrane Library identified randomized controlled trials (RCTs) evaluating PD-1/PD-L1 inhibitors plus SoC compared with SoC alone for LA-HNSCC. The primary endpoints were progression-free survival (PFS), overall survival (OS), locoregional event-free survival (LEFS), and distant metastasis-free survival (DMFS) at the 1-year and 2-year time points, as well as the incidence of grade 3 or higher adverse events (AEs). RESULTS: Four RCTs encompassing 1,818 patients met the inclusion criteria. Compared with SoC alone, PD-1/PD-L1 inhibitors combined with SoC did not significantly improve 1-year or 2-year PFS, OS, LEFS, or DMFS (all p >
0.05). Subgroup analyses further showed no survival benefit at 2 years in the ICI + CRT, ICI + RT-cetuximab, anti-PD-1, or anti-PD-L1 subgroups. Additionally, there was no statistically significant difference in the incidence of grade 3 or higher AEs between the combined and SoC-only groups (p = 0.69). CONCLUSIONS: These findings suggest that adding PD-1/PD-L1 inhibitors to standard therapy does not enhance 1-year or 2-year survival for patients with LA-HNSCC, and confers a similar severe safety profile.