PURPOSE: There is currently limited data on cross-sensitivity between immunotherapy agents. In this case study, we report a case of severe anaphylaxis to both pembrolizumab and cemiplimab. SUMMARY: Pembrolizumab (Keytruda) and cemiplimab (Libtayo) are both approved for the treatment of metastatic cutaneous squamous cell carcinoma. Infusion reactions occur rarely with immunotherapy agents. However, if infusion reactions are severe, the treatment should be discontinued, and there is no guidance as to whether another immunotherapy agent may be used. An 87-year-old-male was diagnosed with metastatic cutaneous squamous cell carcinoma expressing a PD-L1 combined positive score of 81%-90%. He was treated with pembrolizumab and, 15 minutes after completion of the first infusion, developed swelling of the eyelids, ears, and tongue in addition to a whole-body rash without pruritus. Due to the severity of the reaction, pembrolizumab was permanently discontinued and the patient was then started on cemiplimab. The patient received a high-dose corticosteroid as premedication before the first infusion of cemiplimab and tolerated the treatment without any adverse effects. However, when the corticosteroid premedication dose was decreased before the second cycle, the patient had a severe infusion reaction to cemiplimab requiring discontinuation. CONCLUSION: A patient with metastatic cutaneous squamous cell carcinoma developed a severe hypersensitivity reaction to pembrolizumab and subsequently to cemiplimab, despite premedication.