This study investigates the use of cemiplimab, a PD-1 inhibitor, in kidney transplant recipients (KTRs) with advanced cutaneous squamous cell carcinoma (CSCC). The primary objective was to evaluate the rate of kidney allograft rejection, while a secondary objective was to measure antitumor activity. Twelve KTRs with advanced CSCC were enrolled in a phase I clinical trial. Patients were cross-tapered from their existing immunosuppressive regimen to an mTOR inhibitor (sirolimus or everolimus) and pulsed dose prednisone before receiving cemiplimab. No kidney allograft rejection events were observed, and the safety profile was manageable. Five out of 11 evaluable patients demonstrated a response, including three complete responses (CRs) and two partial responses (PRs). The median progression-free survival (PFS) and overall survival (OS) were 22.5 months. Biomarker analyses showed that higher tumor mutational burden (TMB) and increased CD8+ cytotoxic T lymphocytes were potential predictors of response. The study concludes that cemiplimab, combined with mTOR inhibition and pulsed corticosteroids, is a favorable immunosuppressive regimen for KTRs requiring anti-PD-1 therapy, with durable antitumor responses and no observed organ rejection. Future trials are warranted to confirm these findings.This study investigates the use of cemiplimab, a PD-1 inhibitor, in kidney transplant recipients (KTRs) with advanced cutaneous squamous cell carcinoma (CSCC). The primary objective was to evaluate the rate of kidney allograft rejection, while a secondary objective was to measure antitumor activity. Twelve KTRs with advanced CSCC were enrolled in a phase I clinical trial. Patients were cross-tapered from their existing immunosuppressive regimen to an mTOR inhibitor (sirolimus or everolimus) and pulsed dose prednisone before receiving cemiplimab. No kidney allograft rejection events were observed, and the safety profile was manageable. Five out of 11 evaluable patients demonstrated a response, including three complete responses (CRs) and two partial responses (PRs). The median progression-free survival (PFS) and overall survival (OS) were 22.5 months. Biomarker analyses showed that higher tumor mutational burden (TMB) and increased CD8+ cytotoxic T lymphocytes were potential predictors of response. The study concludes that cemiplimab, combined with mTOR inhibition and pulsed corticosteroids, is a favorable immunosuppressive regimen for KTRs requiring anti-PD-1 therapy, with durable antitumor responses and no observed organ rejection. Future trials are warranted to confirm these findings.