S100A10 is one of the members of the S100 protein family and is a key plasminogen receptor. Its upregulation has been reported in many types of tumors. In lung cancer, an association between upregulation of S100A10 and poor prognoses has been reported only in adenocarcinoma. We pursued the possibility of significance in lung squamous cell carcinoma (SCC). We first examined S100A10 protein expression by immunohistochemistry in 120 primary resected lung SCCs; 33 (27.5%) tumors showed strong membranous-immunopositivity particularly at the invasive front, i.e., the cancer-cell surface in contact with the stroma. Expression levels were significantly associated with higher pathological TNM stage (P = 0.0119), tumor size (P = 0.0003), lymphatic invasion (P = 0.0005), lymph node metastasis (P = 0.0006), and poorer prognosis (P = 0.0064). Our present results suggest that high S100A10 expression of the lung SCC cells, particularly adjacent to stroma, plays an important role in tumor progression, probably caused by lymphatic invasion and nodal metastasis.