Purpose <p>Improving the prognosis of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) who have intermediate- and high-risk factors has long been a priority for head and neck surgeons. This study aims to evaluate programmed death-1 (PD-1) inhibitors administered as maintenance monotherapy after standard of care in patients with postoperative intermediate- and high-risk LA-HNSCC.</p> Methods <p>We retrospectively reviewed 47 postoperative intermediate- and high-risk patients with LA-HNSCC who underwent operative interventions between 2016 and 2022. These patients were divided into two groups: a standard therapy group (<i>n</i> = 24) and an adjuvant immunotherapy group (<i>n</i> = 23 standard therapy + immunotherapy). The primary endpoint was 2-year progression-free survival (PFS) and 2-year overall survival (OS). Stratification analysis according to baseline combined positivity score (CPS), with cutoffs set at CPS ≥ 20, was performed to analyze the correlation between CPS and treatment outcomes.</p> Results <p>The 2-year PFS and OS rates in the adjuvant immunotherapy group were 82.6% and 96.0%, respectively, compared to 62.5% (χ2 = 2.376, <i>P</i> = 0.123) and 75.0% (χ2 = 3.646, <i>P</i> = 0.056) in the standard therapy group. Stratified analysis showed that the 2-year PFS and OS rates for patients in the adjuvant immunotherapy group with programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20 significantly improved compared to the standard therapy group (93.3% vs. 62.5%, χ2 = 4.573, <i>P</i> = 0.033), (100.0% vs. 75.0%, χ2 = 4.212, <i>P</i> = 0.040).</p> Conclusion <p>This cohort study found that adjuvant immunotherapy after the standard of care improved PFS and OS in patients with postoperative intermediate- and high-risk LA-HNSCC, especially for those with a PD-L1 CPS of 20 or more.</p>