Primary lung adenocarcinomas and metastatic adenocarcinomas may show a great morphologic resemblance to malignant mesothelioma. There are numerous immunohistochemical markers being used, but none of them were proved to be effective enough to reach a certain diagnosis. The current study was performed to evaluate the utility of thyroid transcription factor-1 (TTF-1) and surfactant protein-B (SP-B) expression in the differential diagnosis between lung adenocarcinomas and pleural mesotheliomas. In this retrospective study, TTF-1 and SP-B were applied to 30 cases with adenocarcinoma and 15 cases with pleural mesothelioma, immunohistochemically, using an avidin-biotin detection system. Twenty percent of adenocarcinomas and 13.3% of pleural mesothelioma stained positive for SP-B. TTF-1 stained 24 of the 30 adenocarcinomas (80%) and none of the 15 mesotheliomas (0%). TTF-1 positivity in adenocarcinomas was found to be statistically significant, while SP-B had no important practical value either used alone or in combination with TTF-1. There was no statistically significant correlation between the differentiation level of adenocarcinomas and TTF-1 staining pattern. In conclusion, we believe that TTF-1 may be helpful in distinguishing lung adenocarcinoma from pleural mesothelioma.