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New developments in the treatment of primary lung cancer have necessitated further pathologic subclassification of nonsmall cell lung carcinomas (NSCLC). Certain therapeutic agents should not be used in squamous cell carcinoma or neoplasms with a dominant squamous component. The aim of this study was to identify the value of immunohistochemical markers p63, thyroid transcription factor-1, and napsin A (novel aspartic proteinase of the pepsin family) in the classification of NSCLC into squamous and nonsquamous subtypes. Thirty cases proved to be NSCLC were selected for this study.Out of 14 squamous cell carcinomas, 12 (85.7%) reacted with p63, whereas only one (7.1%) reacted with thyroid transcription factor (TTF)-1, showing a weak focal staining pattern, and none with napsin A. Out of the 12 adenocarcinomas, eight (66.7%) cases stained for TTF-1, 10 (83.3%) for napsin A, and only one (8.3%) for p63. Out of the four large cell carcinomas, only two (50%) cases reacted with TTF-1, and none with napsin A and p63. Comparing the two markers of lung adenocarcinoma, napsin A showed a higher sensitivity (83.3%) and specificity (100%) than TTF-1 (66.7 and 83.3% respectively).The current results indicate that the use of p63, TTF-1, and napsin A markers may be useful to subclassify NSCLC and to improve therapeutic selection of patients with lung cancer.