OBJECTIVES: To estimate the budget impact (BI) of pembrolizumab for metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults with tumours expressing PD-L1 with a combined proportion score ≥1. METHODS: A BI model was developed in line with the national guidance-informed ‘National Centre for Pharmacoeconomics (NCPE) Budget Impact Template’ developed by the NCPE, the national HTA agency. The perspective is of the drugs budget in the publically funded health system; time horizon is 5 years. Regimens included pembrolizumab monotherapy, pembrolizumab in combination with platinum and 5-fluorouracil (5FU) chemotherapy (combination-therapy), and routine care (incorporating platinum chemotherapy and 5FU, with or without cetuximab), with dosing as per national treatment protocols and the product licenses. Drug costs are estimated using treatment duration data from the KEYNOTE-048 trial. Clinical opinion informed the expected uptake of treatment regimens. Eligibility is estimated based on National Cancer Registry incident case data. Uncertainty is considered using one-way sensitivity analysis and scenario analysis. Costs are VAT inclusive. RESULTS: The estimated cost per patient per treatment course with pembrolizumab is €78,841 and €87,044 for mono- and combination-therapy respectively (cost-year 2020). In 2021, 90 patients are estimated to be treatment eligible, increasing to 96 by 2025. It is assumed that 80% of patients will receive a pembrolizumab regimen (with a 40:60 split between mono- and combination-therapy respectively) and 20% routine care. The estimated 5-year gross BI is €30.55 million. It has been assumed that routine care regimens will be replaced in equal measure, resulting in an estimated 5- year net BI of €25.22 million. Eligible patient population and treatment costs were drivers of uncertainty; estimates ranged from €24.4 million to €36.7 million. Estimates were robust to scenario analysis. CONCLUSIONS: Provision of pembrolizumab treatment for HNSCC in Ireland is associated with an appreciable drugs budget impact.