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No sponsorships or competing interests have been disclosed for this article. Background. Perineural invasion (PNI) in cutaneous squa-mous cell carcinoma of the head and neck (CSCCHN) is associated with decreased survival. Large-nerve PNI pre-sents with clinical signs and symptoms and/or magnetic resonance imaging evidence of cranial nerve involvement. We sought to determine which variables predict a worse outcome and to analyze patterns of failure. Study Design. Case series with planned data collection. Setting. Tertiary care center. Subjects and Methods. Patients with large-nerve PNI from CSCCHN between 1996 and 2006 were identified from a prospectively collected database. Clinical and demographic variables were recorded. Local control rates and survival analysis were performed using Kaplan-Meier curves. Results. Thirty-six patients were identified (28 men and 8 women). The mean age was 61 years. Twenty-nine were treated with curative intent, and 7 received palliation. The mean follow-up was 35 months. Involvement of V3, disease zone, and the type of therapy were significantly associated with overall survival (P \.05). The 5-year disease-free sur-vival for patients by therapy was 50 % for subcranial surgeries, 53.6 % for skull base surgery, and 0 % for radiation and pallia-tive therapies (P \.001). None of the patients treated with a skull base resection had a central recurrence, while all patients who received palliation had a central failure. Conclusions. Disease extent, type of therapy, and involvement of V3 are all significant predictors of survival in PNI from CSCCHN. We confirmed that the natural history of the dis-ease is central progression and that this can be halted, if detected early enough, by a properly planned skull base resection. Keywords perineural spread, cutaneous squamous cell carcinoma, basa