Distinguishing between lung adenocarcinoma and squamous cell carcinoma is becoming increasingly important, as discovery of new advent of targeted therapies, further subtyping of NSCLCs has profound therapeutic implications. Until recently a panel of TTF-1/p63 immunostains is the current recommendation for differentiation of ADC from SqCC in small biopsies or cytological specimens. However, studies using antibodies against p63 have demonstrated false-positive results with positivity in some ADC. P40, a relatively new antibody that targets one p63 isoform -ΔNp63, has been shown a promising marker in identifying SqCC with high sensitivity and specificity compare to P63. In this study, we compared the standard P63 antibody with P40 immunoreactivity in the 160 cases of primary lung carcinoma which included lung ADCs (n=86) and SqCCs (n=74). The p63 was positive in 98.65% of squamous cell carcinomas and 9.23% of adenocarcinomas (sensitivity 98.65%, specificity 93.02%). In contrast, although p40 was also positive in 100% of squamous cell carcinomas, only 1.54% of adenocarcinomas had p40 labeling (sensitivity 100%, specificity 98.83%). Rare adenocarcinomas with p40 labeling had reactivity in no more than 5% of tumor cells, whereas p63-positive cells in adenocarcinomas was >50%. In summary, p40 appears to be a more reliable marker for squamous cell carcinoma as equivalent to p63 in sensitivity, but it is markedly superior to p63 in specificity, which eliminates a potential pitfall of misinterpreting a p63-positive adenocarcinoma as squamous cell carcinoma. In this study, our findings strongly support the routine use of p40 in place of p63 for the diagnosis of pulmonary squamous cell carcinoma.