Aims: To characterise the tumour microenvironment (TME) of head and neck cSCC with perineural invasion (PNI) using image mass cytometry, and to identify immune, clinical and pathological features that differentiate patients who progress to large-nerve perineural spread (PNS) from those who do not. Methods: Patients with head and neck cSCC demonstrating PNI were identified through the Sydney Head and Neck Cancer Institute (SHNCI) database. Corresponding formalin-fixed paraffin-embedded (FFPE) specimens were retrieved from Royal Prince Alfred Hospital Anatomical Pathology. Image mass cytometry was performed using a validated multiplex antibody panel to characterise the tumour microenvironment (TME), including immune cell composition, immune checkpoint expression, and key signalling pathways. Comparative statistical analyses were undertaken between patients who subsequently developed large-nerve perineural spread (PNS) and those who did not. Additional analyses examined the influence of immunosuppression and relevant demographic and clinicopathological variables. Survival outcomes were assessed using Kaplan–Meier methods. Results: Fifty-eight patients with cSCC and confirmed PNI were included; 16 (28%) progressed to large-nerve PNS. TMEs of patients who developed PNS demonstrated a significant reduction in overall immune cell infiltration, most notably across multiple T-cell populations, including all assessed clonal T-cell subsets. No significant differences were observed in B-cell density between cohorts. Conclusion: This study provides one of the first IMC-based characterisations of the immune milieu in head and neck cSCC with PNI. Distinct immune depletion profiles—particularly reduced T-cell subsets—appear to differentiate patients who progress to large-nerve PNS. These findings enhance understanding of the cellular mechanisms underpinning PNS and may inform future immunomodulatory therapeutic strategies and risk-stratification frameworks.