Objective To investigate the expressions of thyroid transcription factor-1(TTF-1), NapsinA, P63 and CK5/6 in lung cancer tissues and their diagnostic value for histological classification. Methods The protein expression in a total of 964 lung cancer samples was detected by immunohistochemistry, of which 929 cases for TTF-1, 113 cases for NapsinA, 282 cases for P63, and 277 for CK5/6, respectively. The correlations between the protein expressions of the four markers and clinicopathological features in lung cancer patients were analyzed. The area under the curves (AUCs) of ROC curves, sensitivity and specificity were calculated to determine the diagnostic values for the four markers. Results There were 552 cases of lung adenocarcinoma (ADC), 146 cases of lung squamous cell carcinoma (SCC), 253 cases of small cell carcinoma (SCLC), and 13 cases of large cell carcinoma (LCC). The median age was 56 years old, and 63.4% was male. The positive expression rates of TTF-1, NapsinA, P63, and CK5/6 were 76.3% (709/929), 67.3% (76/113) , 47.2% (133/282) and 34.7% (96/277), respectively. The positive expression rates of TTF-1 and NapsinA were higher in lung ADC, and the sensitivity and specificity of TTF-1 in the diagnosis of ADC were 81.15% and 30.41% respectively, those of NapsinA were 82.05% and 65.71% respectively. The AUCs for TTF-1 and NapsinA were 0.557 8 (P=0.002 6,95%CI：0.520 0-0.595 6) and 0.738 8 (PCI:0.633 4-0.844 2) respectively. The positive expression rates of P63 and CK5/6 were significantly higher in lung SCC, and their sensitivities to diagnose SCC were 80.68% and
