Background: The use of sentinel lymph node biopsy (SLNB) for high-risk cutaneous squamous cell carcinoma (CSCC) is not yet clearly documented, especially for the head and neck area, due to its rich and cross-branching lymphatic system. We present the first prospective randomized study on the use of SLNB in high-risk CSCCs of the head and neck., Methods: Seventy-six patients with high-risk CSCCs of the head and neck were randomly divided into two groups: A (n = 38) and B (n = 38). In group A, SLNB was performed additionally to the excision of squamous cell carcinoma, whereas in group B, only excision of the lesion was performed. The patients were followed up for 5 years postoperatively, and local recurrences, regional metastases (regional lymph nodes), and mortality were documented., Results: One patient of group A, who never attended any follow-up, was excluded. Both groups had similar characteristics regarding Breslow thickness, perineurial invasion, peripheral limits, differentiation, size, previous incomplete excision, age, sex, education, sun exposure, Fitzpatrick score, previous incomplete excision, previous skin cancer, and smoking. Two patients had a positive sentinel lymph node and were submitted to regional lymphadenectomy. We documented deaths (three in group A and two in group B; P = 0.674), local recurrence (seven in group A and six in group B; P = 0.768), and regional metastasis (zero in group A and two in group B; P = 0.159)., Conclusion: There is no clear benefit on the use of SLNB in high-risk CSCCs of the head and neck regarding metastasis, mortality, or local recurrence control., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)