Abstract Background: Cancer associated fibroblasts (CAFs) are main components of tumor microenvirnoment. They act an essential role in tumor progression, invasion and unrespon-siveness to chemotherapy. Aim of Study: This work aims to study the relation of CAFs with hepatocellular carcinoma (HCC) developement and progression. Material and Methods: This is an uncontrolled retrospec-tive study carried upon 30 cases of HCC. Cases were collected from archives of Pathology Department and Early Cancer Detection Unit (ECDU), Faculty of Medicine, Benha Univer-sity, and from International Medical Center during the years 2010-2015. Podoplanin (D2-40), alpha smooth muscle actin (a-SMA) and CD31 immunohistochemichal staining were performed and evaluated for each case. Results: Both D2-40 and a-SMA showed different distri-butions and levels of expression. D2-40 positivity was localized to the peri-tumoral area, while a-SMA was detected in both intra- and peritumoral areas. Expression of both markers was not statistically related to each other (p>0.05). D2-40 was positive in 73.3% of casesand a-SMA showed high expres-sionin 60% of cases. Both positive D2-40 and high a-SMA showed positive relations to tumor grade (p