Background: Accurate sub-classification of non-small cell lung carcinoma (NSCLC) is crucial for the targeted therapy. In lung cancer most of tumors are un-respectable at diagnosis and small biopsy or cytological specimen is commonly the only available material for histopathology diagnosis. Although most of NSCLC can be diagnosed by routine stains, however diagnosis of poorly differentiated or undifferentiated tumors in small biopsy is challenging. Objective: To evaluate the diagnostic value of Napsin A immunohistochemical (IHC) marker in NSCLC small biopsy. Materials and Methods: Forty-six cases of primary NSCLC diagnosed by biopsy with subsequent resection were enrolled in this study. Subtyping of tumors was done according to 2015 World Health Organization criteria. IHC expression of Napsin A was assessed for all the cases. For large cell carcinoma (LCC) cases, Thyroid Transcription Factor 1 (TTF-1) and P63 expression were also tested. Markers expression was correlated with the histological diagnosis of the tumor. Sensitivity, specificity, positive, negative predictive values, and total accuracy of the markers were calculated. Result: In NSCLC cases, the diagnostic sensitivity and specificity of Napsin A were 85.2% and 75% (respectively) with a PPV of 85.2%, NPV of 75.0% and 81.4% accuracy. In LCC cases TTF1 sensitivity was 57.1% and specificity 100%, PPV 100%, NPV 14.3%, accuracy 60.0%. In LCC P63 marker had a diagnostic sensitivity, specificity, PPV, NPV and accuracy of 100%, 85.7%, and 33.3%, 100.0% and 86.7% respectively. Expression of both Napsin A and TTF 1 in LCC cases raised the accuracy to 86.7%. Conclusions: In small biopsy specimens Napsin A can subtype NSCLC with high sensitivity and moderate specificity. Additions of TTF-1/p63 IHC markers can further enhance the accuracy.