Purpose <p>To compare the efficacy of induction chemotherapy with or without PD-1 inhibitors followed by chemoradiotherapy (CCRT) among patients with human papillomavirus (HPV)-negative locally advanced head and neck squamous cell carcinoma (LA-HNSCC).</p> Materials and methods <p>We retrospectively reviewed patients with HPV-negative LA-HNSCC who received induction chemotherapy with or without PD-1 inhibitors followed by CCRT between January 2018 and June 2023. Overall survival (OS), disease-free survival (DFS), and treatment-related adverse effects (TRAEs) were compared between the two groups overall and then in one-to-one propensity-score matched (PSM) cohorts.</p> Results <p>A total of 289 eligible patients were enrolled, with 120 patients received induction chemotherapy (the IC group), and 169 patients received induction chemotherapy combined with PD-1 inhibitors (the IC-IO group). Median follow-up was 39.3&#xa0;months (range: 37.5–41.5&#xa0;months). After PSM, objective response rate (ORR) was not significantly different in the IC-IO group versus the IC group (81.5% vs 74.1%, <i>P</i> = 0.19). The IC-IO group (vs. the IC group) had a superior 2-year OS (84.3% vs. 68.2%, <i>P</i> = 0.002) and DFS (74.1% vs. 56.9%, <i>P</i> = 0.005). G3/4 TRAEs between the two matched groups were comparable both during induction (11.1% vs 11.1%, <i>P</i> = 1.000) or CCRT (29.6% vs 38.9%, <i>P</i> = 0.152) phases. For the IC-IO group, no significant differences in OS (<i>P</i> = 0.68) or DFS (<i>P</i> = 0.29) were observed in the subset with versus without PD-1 inhibitors concurrently with CCRT.</p> Conclusions <p>The addition of PD-1 inhibitors to IC significantly improves outcomes with tolerable TRAEs in patients with HPV-negative LA-HNSCC.</p>