Objectives: Osteopontin is a multifunctional protein molecule that plays an important role in the development and progression of malignant tumors. Its action is achieved via integrin receptor molecules or the non-integrin receptor (CD44v6), and acts on the processes of proliferation, apoptosis, angiogenesis, invasion and metastasis. The aim of this study was to investigate the expression of osteopontin in normal lung tissue, in tumor tissue non-small cell lung cancer (NSCLC) and its major histologic subtypes, to examine the relationship of osteopontin to clinicopathological parameters such as tumor size, degree of differentiation, lymph node status, pT, TNM and five-year survival, to examine the relationship of osteopontin and its receptor molecules in the tumor cells, and to assess the possible effect of osteopontin on apoptosis and the proliferation of tumor cells. Patients and Methods: The expression of osteopontin and its receptor molecules, as well as the proliferative activity of tumor cells (Ki67) was investigated by an immunohistochemical method using tissue microarrays from precise tumor regions (central tumor tissue, invasive front and metastatic tissue) of 110 NSCLC, while the apoptotic activity of the cells was determined by the TUNEL method. Osteopontin expression was compared to the clinicopathological parameters, expression of αv-integrins and CD44v6 molecule, and the proliferation index and apoptosis index. Results: Expression of osteopontin and its receptor molecules in the tumor tissue is stronger than in the normal lung tissue. In the NSCLC group, osteopontin expression was stronger in adenocarcinomas (p <0.001), and the expression of αv-integrins (p <0.001) and molecules CD44v6 (p <0.001) was stronger in squamous cell carcinoma. No significant correlation was noticed between the expression of osteopontin and clinicopathological parameters. VI Osteopontin expression was stronger in invasive front of adenocarcinoma (p = 0.041) and squamous cell carcinoma (p = 0.011) compared to the central tumor region, and in metastatic tissue of NSCLC group (p = 0.042) compared to the primary tumor. We observed highly expressed osteopontin in well differentiated tumor regions of NSCLC (p=0.006), higher αv-integrin (p=0.038) and CD44v6 (p=0.001) expression in the areas of lower differentiated adenocarcinoma, and highly expressed molecule CD44v6 in well differentiated areas of squamous cell carcinoma (p=0.011). Among the histological subtypes apoptotic activity was not significantly different (p=0.455), whereas the proliferative activity was higher in squamous cell carcinoma (p<0.001). Expression of osteopontin in adenocarcinomas is associated with a low index of apoptosis (p = 0.006) suggesting an antiapoptotic role of osteopontin. A positive correlation between expressions of osteopontin and αv-integrin in initial lung adenocarcinomas stage was found (p=0.033), as well as strong positive correlation of expressions of the two receptor molecules in a NSCLC group (p<0.001) and squamous cell carcinomas group (p=0.008), when the simultaneous co-expression of osteopontin and αv-integrin correlated with low apoptotic index (p <0.01). The positive lymph node status and higher TNM stage are associated with shorter survival. Conclusion: In adenocarcinoma, osteopontin overexpression is associated with low apoptotic index, probably through the activation of an αv-integrin receptor molecule. As a result, osteopontin promotes the survival of tumor cells. A stronger expression of osteopontin in the invasive front of the tumor and metastasis suggests a role in the progression and metastasis of NSCLC.