Background: The preferred treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) not amenable to localized/curative treatment is pembrolizumab, either monotherapy or in combination with chemotherapy based on the results of KEYNOTE-048. Since the FDA’s approval of pembrolizumab in 2019, real-world data has been scarce. Using the TriNetX platform, we retrospectively compared survival outcomes between patients treated with pembrolizumab vs. cetuximab-based treatment. Methods: Cohorts were identified on TriNetX platform using the US Collaborative Network, which includes anonymous clinical information of patients between 2007-2023. Three cohorts were selected: patients treated with pembrolizumab monotherapy (P), patients treated with pembrolizumab and platinum+5-FU chemotherapy (P+CT), and patients treated with cetuximab and platinum+5-FU chemotherapy (C+CT). All patients had non-nasopharyngeal R/M HNSCC with no prior systemic therapy. The study objective was to compare overall survival (OS) between these three cohorts using the Kaplan-Meier method. Results: Our analysis identified 409 patients in cohort P, 161 patients in cohort P+CT, and 176 patients in cohort C+CT. Median age at initiation of treatment was 69.8, 62.2, and 57.7 years in cohort P, P+CT, and C+CT, respectively. Male percentage was 61%, 75%, and 77%, respectively. The most common primary tumor sites for cohorts P, P+CT, and C+CT were as follows: oropharynx 28%, 37%, and 48%, hypopharynx 10%, 19%, and 11%, larynx 31%, 29%, and 40%, and oral cavity 4%, 6% and 9% respectively. Information on PD-L1 and HPV (Human Papillomavirus) status was not available. Median OS was 13.7, 15, and11.4 months in cohorts P, P+CT, and C+CT, respectively. Survival probability at 5 years was 25.7% in cohort P, 32.2% in cohort P+CT, and 9.9% in cohort C+CT. Based on our analysis, patients treated with pembrolizumab (P or P+CT) demonstrated superior OS compared to those who received cetuximab-based therapy (P-Value <0.05). There was no statistically difference in median OS between P and P+CT group. (P-Value 0.6). Conclusions: Our retrospective analysis of real-world data from a large national database shows superior OS with pembrolizumab- based treatment compared to cetuximab-based treatment in the first line setting for patients with R/M HNSCC. This analysis is consistent with KEYNOTE-048 outcomes. we found no difference in OS between Pembrolizumab alone or in combination with chemotherapy. Limitations include unknown PD-L1 and HPV status. Further long-term and prospective analysis is imperative to enhance the care and outcomes of patients with metastatic HNSCC.