Background: Nearly 1.5 million cases of cutaneous squamous cell cancer (cSCC) are diagnosed annually in the United States. Approximately 1% of cases are in the advanced unresectable stage. The standard of care in unresectable advanced disease is immunotherapy with anti-PD-1 agents. Cemiplimab, an anti-PD-1 antibody, was approved by the Food and Drug Administration in 2018. We present real-world clinical data from a single institution on outcomes and safety for patients treated with cemiplimab for metastatic and unresectable cSCC. Methods: We conducted a retrospective cohort analysis of patients treated with cemiplimab (350 mg every 3 weeks) for advanced cSCC from September 2018 until December 2021. Data included patient demographics, tumor characteristics, and treatment course. Patients who received at least 1 dose of cemiplimab and one clinic follow-up were included for analysis. Clinical response and adverse events (AE) were evaluated. Results: Of the 26 patients treated, 84% were male (n = 22), and 16% were female (n = 4) with a median age of 74 years (39-94). Twenty-three (23) patients were included in the final analysis as 3 patients transferred care to an outside facility and were not available for follow-up. Nineteen (19) patients (73%) had locally advanced disease and 7 (27%) had metastatic disease. The most common site of the primary tumor was head/neck (85%, n = 22) with all remaining cases on the trunk/extremities (15%, n = 4). Patients received a median of 7 doses of cemiplimab (range 1- 46). The median time to first response was 1.7 months which required a median of 2.5 doses. An objective clinical response defined as complete response (CR) or partial response (PR) was seen in 18/23 (78%) patients, of whom 8/23(35%) were CR and 10/23 (44%) PR. The ongoing response was noted in 6/23 (27%) with continued treatment. Treatment was well-tolerated with 6/23 (26%) adverse events (AE) all of which were grade 1 or 2: 1 (4%) grade 1 pruritus, 5 (21.7%) grade 2. Of the 5 grade 2 AEs, 1 was infusion-related, 2 hypothyroidism, 1 dermatitis, 1 rheumatoid arthritis flare. No grade 3-5 AEs were noted. Conclusions: To the best of our knowledge, this is the first real-world outcomes study of advanced cSCC patients treated with cemiplimab in the United States. The overall efficacy, response rate, and safety profile were better in comparison to the results of the EMPOWER-CSCC-1 trial.