This study aimed at evaluating the utility of a panel of antibodies, consisting of cytokeratins (CK) 5/6, CK34βE12, p63, thyroid transcription factor-1 (TTF-1), and CK7 for distinguishing between squamous cell carcinoma (SCC) and adenocarcinomas (Ad), as well as their expression with clinicopathological parameters and prognosis in SCC and Ad. 111 SCC of small biopsy specimens and 99 cases of Ad were stained by immunohistochemistry, among which 76 SCC and 64 Ad had complete follow-up data. Most of SCC displayed CK5/6 (91/99, 91.92%), CK34βE12 (83/99, 83.84%), p63 (96/99, 96.97%), and most of Ad showed expression of CK7 (89/111, 80.18%) and TTF-1 (105/111, 94.59%). The combination of CK5/6/CK34βE12/p63 seems to be useful for differentiating SCC from Ad with 100% sensitivity and 97.30% specificity, and TTF-1 was a useful biomarker for Ad with 94.59% sensitivity and 100% specificity. There were differences between CK5/6, p63, and TTF-1 expression with tumor differentiation (p<0.05) in SCC or Ad. Univariate analysis indicated that patients with high TTF-1 expression predicted better prognosis in Ad patients. Multivariate analysis showed that TTF-1 expression (HR=0.340, 95% CI 0.143-0.811, p=0.015) was a good independent predictor of Ad patient survival.