Hepatocellular carcinoma (HCC) is the final sequel of prolonged chronic hepatitis B. Integrated network among cancer cells and various stromal cells exist in the HCC tumour microenvironment (TME) have profound impact on the progression of this disease. Emerging evidences depict that extracellular vesicles (EVs) released by the cells are the potent mediators in this partnership. These vesicles carry cell specific active molecules such as protein, nucleic acids (DNA, coding and non-coding RNAs), lipid etc. In this respect, the impact of hepatitis B virus (HBV) on the packaging of cargo molecules of the infected hepatocytes and its effect on the disease progression has not been investigated. Thus, label-free proteomics analysis was performed in triplicates with the EV protein content of HBV infected HepG2.2.15, and HepG2-control cells using label-free LC-MS/MS technology and observed 2293 and 677 proteins respectively suggesting HBV induced 3.4 fold more accumulation of proteins in the EVs. Among which, 512 proteins were differentially enriched in the EVs of HepG2.2.15 cells. Pathway analysis performed with 103 proteins which showed intracellular abundance depicted that DNA repair, RNA metabolism and Golgi trafficking proteins were enriched in the EVs of HepG2.2.15 cells.