Objectives: The KEYNOTE-048 trial indicated pembrolizumab plus chemotherapy is an appropriate first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), while pembrolizumab monotherapy is optimal for PD-L1 positive patient. This study was powered to determine the most cost-effective strategy for patient with different combined positive score (CPS). Materials and methods: A Markov model was developed to predict progression-free survival, disease progression, or death in patients with recurrent or metastatic HNSCC based on data from the KEYNOTE-048 trial. Cost was obtained from West China Hospital, while utilities were referred to published studies. By using Monte Carlo simulations, acceptability curves were depicted to address the uncertainty of model inputs. Results: Compared with cetuximab plus chemotherapy, pembrolizumab monotherapy resulted in an incremental cost-effectiveness ratio (ICER) of $14,995 per quality adjusted life year (QALY) in total population and $22,779 per QALY in patients with CPS ≥ 1. Comparing pembrolizumab plus chemotherapy with standard therapy led to an ICER of $43,230 per QALY in total population and $26,157 per QALY in patients with CPS ≥ 1. For patients with CPS ≥ 20, ICERs yield by immunotherapy with or without chemotherapy exceeded the threshold of willingness to pay we set, when compared with standard therapy. Pembrolizumab plus chemotherapy was dominated by pembrolizumab alone in this patient population. Conclusion: For HNSCC patients with different CPS, pembrolizumab alone was the optimal choice for total population and patients with CPS ≥ 1. Among patients with high CPS, immunotherapy with or without chemotherapy was not preferred over the standard therapy. © 2020 Elsevier Ltd