Background: P63 is a gene located in chromosome 3q27-29, which has been implicated in regulation of stem cell commitment and promotion of squamous differentiation in various tissues. The aim of this study was to investigate whether there was a correlation between p63 expression, differential diagnosis of lung carcinoma, and prognosis. Material/Methods: Immunohistochemical expression of p63 in 62 lung carcinomas was investigated and mRNA analysis using RT-PCR method was done in 6 selected cases. Results: When cases were evaluated for p63 staining, 24 of 25 (96%) squamous cell carcinomas were strongly positive. Six of 20 adenocarcinomas (25%) and 1 (100%) large cell carcinoma (except neuroendocrine carcinoma) were mildly positive. p63 staining was statistically significant in favor of squamous cell carcinoma than other tumors (p<0.001). Forty percent of squamous cell carcinomas had squamous carcinoma in situ, whereas adenocarcinomas had none. There was a significant statistical difference between squamous cell carcinoma and adenocarcinoma (p=0.002). p63 was strongly positive in all of 12 squamous carcinoma in situ cases. In 6 cases where mRNA analysis was performed by RT-PCR method, DNp63 was strongly positive in 3 squamous cell carcinomas, mildly positive in 1 adenocarcinoma, and negative in 1 carcinoid tumor. TAp63 was strongly positive in non-tumoral lung tissue but negative in all tumors, except 1 squamous cell carcinoma. Conclusions: Our data suggest that poorly differentiated squamous cell carcinoma had strong and widespread staining for immunohistochemical expression of p63. Therefore, p63 can be a useful marker in differentiating squamous cell carcinoma from poorly differentiated adenocarcinoma and squamous cell carcinoma from large cell neuroendocrine carcinoma. © Med Sci Monit.