Sox2 has been related to cell cycle regulation, stemness and cancer development. It has gained noticeable importance due to its expression in malignancies at different sites including lung cancer. In a trial to improve the unfavorable prognosis of patients suffering from lung cancer especially those with non-small cell lung cancer (NSCLC), this study targets the possible underlying mechanisms of Sox2 in cases of NSCLC using the immunohistochemical expression of Sox2. Forty patients of NSCLC, 18 squamous cell carcinomas (SCC) and 22 adenocarcinomas (AC), were enrolled and evaluated for Sox2 expression. Sox2 was positive in 78% of SCC, and 45.5% of AC. A significant increase of positive Sox2 expression was found in SCC (p=0.04), tumor stage IV (p=0.04) and lower tumor grades (p=0.02). The relation between Sox2 expression and tumor grade and stage in SCC against AC cases showed that positive expression was associated with higher stage and lower grades (p=0.04 for both). The correlation between Sox2 scores and tumor stage and grade among the studied cases showed that Sox2 scores was positively correlated stage (r=0.37, p=0.02) and negatively correlated with tumor grades (r= -0.40, p=0.01). Sox2 positivity points to higher stages and its negativity points to higher grade differentiation, so it could be considered poor prognostic factor. Sox2 has direct role in lung cancer development and its knockdown might be beneficial in overcoming therapeutic resistance.