The recent development of human genome studies has demonstrated the possibility of alteration of several genes as oncogenic driver mutations of lung squamous cell carcinoma (SQCC). FGFR1, PIK3CA and SOX2 genes have been recognized as candidate driver genes of SQCC. The aim of the present study was to evaluate FGFR1, PIK3CA and SOX2 protein expression in SQCC and determine whether the expression of these can be used as prognostic biomarkers. We evaluated the relationships between FGFR1, PIK3CA and SOX2 expression by immunohistochemical analysis and overall survival in lung SQCC patients with stage I-III that originated from China, United States and Japan. FGFR1-positive, PIK3CA-negative and SOX2-positive staining each showed trends toward better survival, although the differences were not statistically significant in a Chinese cohort of 57 patients. Patients with PIK3CA-negative and SOX2-positive staining (PIK3CA(-)/SOX2(+)) showed better prognosis compared with those with PIK3CA-positive or SOX2-negative staining in the Chinese cohort (p=0.04). The robustness of PIK3CA(-)/SOX2(+) classification as having prognostic significance was validated in an independent set of 66 Japanese cohort patients (p=0.007). Japanese SQCC patients with stage I were evaluated separately and PIK3CA(-)/SOX2(+) cases had significantly better survival than the group with PIK3CA-positive or SOX2-negative status (p=0.03). In univariate and multivariable Cox proportional hazards models of Asian stage I patients, the PIK3CA(-)/SOX2(+) classification was statistically significantly associated with survival and was an independent prognostic factor. Classification by PIK3CA and SOX2 protein expression is useful for predicting the prognosis of Asian patients with lung SQCC with stage I.