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BACKGROUND SOX18 is an integral transcription factor that is involved in endothelial cells differentiation during both angiogenesis and lymphangiogenesis. Therefore, it has been implicated in tumor progression and metastasis. OBJECTIVE To study SOX18 expression in nonmelanoma skin cancers (NMSCs) in comparison to seborrheic keratosis (SK) and normal control skin, and to assess its probable role in tumor evolution and progression. PATIENTS AND METHODS This study was conducted on 60 specimens of NMSCs: 30 basal cell carcinomas (BCC) and 30 squamous cell carcinomas (SCC), 30 specimens of SK, and 30 normal skin specimens. All were examined for immunohistochemical expression of SOX18 antibody. Additionally, morphometric assessment of vessel density (blood & lymphatic) in each specimen was estimated. RESULTS Significant SOX18 overexpression was observed in all studied cutaneous tumors in comparison to control skin. The highest score of SOX18 expression was detected in SCC, then BCC, and the least expression was reported in SK with significant difference between them. Furthermore, significant upregulation of SOX18 expression was observed in high-risk types of both BCC and SCC compared to low-risk types. Stromal vessel density showed significant differences between the studied tumors with the highest mean value in SCC, followed by BCC and then SK. Positive correlation between SOX18 expression in the studied tumors and their vessel density was detected. CONCLUSIONS SOX18 may have a potential role in the evolution as well as progression of NMSCs, possibly through induction of both angiogenesis and lymphangiogenesis. Furthermore, it could be beneficial for prediction of NMSC patients with poor prognosis.