Background: Recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC) presents significant therapeutic challenges. While cetuximab (EGFR inhibitor) and immune checkpoint inhibitors (ICIs) have improved outcomes, optimal treatment sequencing remains undefined. Methods: This retrospective analysis evaluated 822 RMHNSCC patients treated between January 2016 and December 2022 across multiple Taiwanese centers. Patients received either cetuximab monotherapy (n=401), ICI monotherapy (n=248), or sequential therapy with both agents (n=173). Sequential therapy comprised cetuximab followed by ICI (C→I, n=102) or ICI followed by cetuximab (I→C, n=71). Primary endpoint was overall survival (OS), with progression-free survival (PFS), objective response rate (ORR), and adverse events as secondary endpoints. Results: At median follow-up of 31.4 months, ICI monotherapy demonstrated significantly improved median OS versus cetuximab monotherapy (13.2 vs. 9.4 months; hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.61-0.86; p=0.001). Sequential therapy showed median OS of 14.8 months, significantly higher than cetuximab monotherapy (HR 0.68; 95% CI 0.56-0.83; p<0.001) but comparable to ICI monotherapy (HR 0.91; 95% CI 0.74-1.13; p=0.39). The sequence of administration (C→I vs. I→C) did not significantly impact OS (15.1 vs. 14.5 months; HR 0.94; 95% CI 0.67-1.31; p=0.72). Multivariable analysis confirmed these findings after adjusting for confounding factors. Conclusion: Our findings establish ICI therapy’s superior efficacy over cetuximab monotherapy in RMHNSCC patients, aligning with previous clinical trials. Sequential therapy with both agents provides additional clinical benefit regardless of administration sequence. This suggests both approaches (C→I and I→C) are effective options, offering clinicians flexibility in treatment planning based on individual patient characteristics, comorbidities, and treatment history. Further prospective studies are needed to identify biomarkers for optimal treatment selection and sequencing in this challenging population.