Background <p>Recent studies suggested that neoadjuvant cemiplimab can achieve a significant pathologic response in patients with cutaneous squamous cell carcinoma (CSCC). This was a retrospective cohort study (2018–2021) to determine whether response-adapted oncologic surgery (RAOS) can reduce surgical morbidity while maintaining oncological safety, thus offering a viable alternative to standard resection.</p> Patients and Methods <p>A total of 41 patients with head and neck CSCC were treated with neoadjuvant cemiplimab followed by surgery, either RAOS or standard resection. The extent of the intended surgery (i.e., standard resection) was defined using a 10-mm margin from the clinically measured lesion. RAOS was defined as any resection smaller than the intended surgery. Main outcomes were surgical margins, local recurrence-free survival rates, organ preservation, need for free-flap reconstruction, and pathologic response, compared between the surgical groups.</p> Results <p>A total of 17 patients underwent RAOS and 24 patients underwent standard resection. Neoadjuvant treatment allowed for organ preservation in four (24%) patients in the RAOS group, and four (24%) patients in the RAOS group who were meant to have free-flap reconstruction did not need a free flap after resection. Clear margins were achieved in 16 (94%) patients in the RAOS group and 22 (92%) patients in the standard resection group (<i>p</i> = 0.3). The 2-year locoregional recurrence-free survival rate was 95% for the RAOS group and 90% for the standard resection group (<i>p</i> = 0.4).</p> Conclusions <p>RAOS following neoadjuvant cemiplimab for CSCC appears oncologically safe and has similar survival outcomes to and less surgical morbidity than standard resection. Further prospective studies are needed to confirm these findings.</p>