Radixin is a member of the ERM (ezrin/radixin/moesin) protein family that is proposed to function as a membrane-cytoskeletal linker. Using differential display analysis, we have identified radixin as a gene down-regulated in primary lung adenocarcinoma. Real-time quantitative reverse transcription polymerase chain reaction confirmed that radixin mRNA was decreased, both in 10 early-stage bronchioloalveolar carcinomas and in 16 invasive lung adenocarcinomas, by 69% (p = 0.0002) and 82% (p < 0.0001), respectively, compared with 9 nontumor lung tissues. Similarly, moesin and ezrin mRNA levels were reduced in lung adenocarcinoma. Immunohistochemistry confirmed that cancer cells expressed very little radixin and moesin, whereas non-neoplastic alveolar and bronchiolar epithelial cells, and endothelial cells, including those within the tumor stroma, were consistently positive for these two proteins. Ezrin was localized in the apical surface of non-neoplastic bronchiolar and alveolar epithelial cells and, in contrast to radixin and moesin, the majority of tumor cells retained expression of ezrin. Localization of ezrin was altered in a significant proportion of tumor cells: whereas tumor cells forming lumina displayed membranous staining on the apical side, tumor cells with disorganized structures were either negative or diffusely positive for ezrin in the cytoplasm. Furthermore, a fraction of tumor cells invading the stroma in a scattered manner were strongly positive for ezrin. In conclusion, expression of radixin and moesin is down-regulated in lung adenocarcinoma, including early-stage bronchioloalveolar carcinoma. An intriguing implication of this finding is that these two genes may function as tumor suppressors in lung adenocarcinoma oncogenesis. Although structurally related to radixin and moesin, ezrin may have a distinct function in tumor-cell invasion.