Cutaneous squamous cell carcinoma (cSCC) is a common malignancy worldwide, responsible for 20% of all skin cancer cases, and the first as the cause of death from keratinocytic carcinomas. Around 5% of primary cSCCs metastasize to regional or distant body parts, leading to a 5-year survival rate of only 25-35%. Currently, clinical and histopathological assessment is used for the diagnosis of metastatic cSCC, and this is when the disease is already metastasised. Therapies for patients with metastatic cSCCs are lacking due to poor knowledge of the molecular alterations that drive this metastasis. In this paper, we used liquid chromatography coupled with SWATH mass spectrometry workflow to analyse formalin-fixed and paraffin-embedded samples of primary (n=20) and metastatic cSCC (n=25) for the identification of protein biomarkers and molecular alterations discriminating between the lesion groups. We quantified 5037 proteins across all the samples studied of which 19 proteins including TBD2A, GCP60 and PDLI3 were increased and 11 proteins including CBPA3, SAMP and DMKN were decreased respectively in metastatic cSCC relative to the primary phenotype (adj. p-value < 0.05; fold change ± 1.8). The proteomics data also separated the two lesion groups on principal components analysis. Bioinformatics analysis revealed that Ras protein signalling, small GTPase mediated signalling and regulation of cytoskeleton organisation were associated with cSCC metastasis. Overall, results from this study showed excellent potential to discriminate between primary and metastatic cSCC subtypes, facilitating new diagnostic and therapeutic strategies.