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Background: Vulvar cancer treatment is mostly curative, but also has high morbidity rates. In a search for markers that can identify patients at risk of metastases, we investigated the prognostic value of L1-cell adhesion molecule (L1CAM) in large series of vulvar squamous cell carcinomas (VSCCs). L1CAM promotes cell motility and is an emerging prognostic factor for metastasis in many cancer subtypes., Results: L1CAM expression was observed at the invasive front or in spray-patterned parts of 17% of the tumours. L1CAM-positive tumours expressed vimentin more often, but L1CAM expression was not associated with TP53 or CTNNB1 mutations. Five-year survival was worse for patients with L1CAM expression (overall survival 46.1% vs 63.6%, P=.014, disease specific survival 63.8% vs 80.0%, P=.018). Multivariate analysis indicates L1CAM expression as an independent prognostic marker (HR 2.9, 95% CI 1.10-7.68). An in vitro spheroid invasion assay showed decreased invasion of L1CAM-expressing VSCC spindle cells after treatment with L1CAM-neutralising antibodies., Methods: Paraffin-embedded tumour tissue from two cohorts (N=103 and 245) of primary VSCCs were stained for L1CAM, vimentin and E-cadherin. Patients of the first cohort were tested for human papilloma virus infection and sequenced for TP53 and CTNNB1 (β-catenin) mutations. The expression of L1CAM was correlated to clinical characteristics and patient survival., Conclusion: This is the first study to show high L1CAM-expression at the infiltrating margin of VSCC's. L1CAM-expressing VSCCs had a significantly worse prognosis compared to L1CAM-negative tumours. The highest expression was observed in spindle-shaped cells, where it might be correlated to their invasive capacity., Competing Interests: The authors declare no conflicts of interest.