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Cancer\u2010associated fibroblasts (CAFs) promote progression of cancer, but their role in cSCC is largely unknown. We examined the potential of CAF markers in the assessment of metastasis risk and prognosis of primary cSCC. We utilized multiplexed fluorescence immunohistochemistry for profiling CAF landscape in metastatic and non\u2010metastatic primary human cSCCs, in metastases, and in premalignant epidermal lesions. Quantitative high\u2010resolution image analysis was performed with two separate panels of antibodies for CAF markers and results were correlated with clinical and histopathological parameters including disease\u2010specific mortality. Increased stromal expression of fibroblast activation protein (FAP), \u03b1\u2010smooth muscle actin, and secreted protein acidic and rich in cysteine (SPARC) were associated with progression to invasive cSCC. Elevation of FAP and platelet\u2010derived growth factor receptor\u2010\u03b2 (PDGFR\u03b2) expression was associated with metastasis risk of primary cSCCs. High expression of PDGFR\u03b2 and periostin correlated with poor prognosis. Multimarker combination defined CAF subset, PDGFR\u03b1\u2212\/PDGFR\u03b2+\/FAP+, was associated with invasion and metastasis, and independently predicted poor disease\u2010specific survival. 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