Background: Pembrolizumab and Nivolumab are PD-1 inhibiting immunotherapy agents approved for the treatment of metastatic or recurrent head and neck squamous cell carcinoma in patients previously treated with platinum-based chemotherapy. Both therapies have demonstrated similar survival benefits and adverse event profiles, but there is no published comparison of treatment cost and survival between the two agents. This study aims to analyze the cost-effectiveness of pembrolizumab compared to nivolumab through network meta-analysis techniques. Methods: Data published from the KEYNOTE-040 (pembrolizumab) and CheckMate 141 (nivolumab) studies were used to generate a model incorporating the cost of each drug in both the arms. The cost of treatment of side effects was extracted from previously published data and used for cost estimation in the model. Data from the standard of care arms (cetuximab, methotrexate, or docetaxel) in each study were adjusted to provide a common reference between the two studies. The number of years added in terms of overall survival was calculated for the entire experimental arm and the cost of each such year was calculated. All costs were adjusted for inflation. Results: Using published data from the KENOTE-040 trial, the average cost per patient adjusted for inflation over time, over 24 months in the pembrolizumab arm was $159,302, and similarly using data from the Checkmate 141 trial, the average cost per patient over 18 months in the nivolumab arm was $118,790. The cost of management of adverse effects was $18,728 vs $16,685 (pembrolizumab vs. nivolumab) during these time periods. Our model suggests that the adjusted total cost per month for patients on these drugs is very similar: $7417.91 vs. $7526.38. Assuming that the quality of life was similar in both groups and using an average OS for the standard of care arms, our model predicts that ICER for pembrolizumab is higher than nivolumab ($203,085 vs. 132,644). Conclusions: Both pembrolizumab and nivolumab improve survival benefit compared to their respective standard of care arms. However, the ICER for both medications is higher than the threshold set by many payers and health provider organizations. The model makes several assumptions which may render it less accurate to compare between trials but the cost of treatment for both drugs is not in the cost-effective range. To utilize these drugs in a cost-conscious practice, further research is needed to investigate lower doses at a slower frequency along with reduction of the price for each medication.