Human hepatocellular carcinoma is one of the most common recurrent malignancies since there is no effective therapy for it. Silibinin, a widely used drug and supplement for various liver disorders, demonstrated anti-cancer effects on human hepatocellular carcinoma, human prostate adenocarcinoma cells, human breast carcinoma cells, human ectocervical carcinoma cells, and human colon cancer cells. Considering the anti-hepatotoxic activity of silibinin and its strong preventive and anti-cancer efficacy against various epithelial cancers, we investigated the efficacy of silibinin against human HCC and HUVEC cell lines. Silibinin effects on the growth and mode of cell death of these two cell lines are presented in this paper. HepG2 and HUVEC cells were incubated with different doses of silibinin (12.5, 25, 50, 100, 150 and 200 μg/mL) at 24, 48, and 72 h. Cytotoxicity was assessed using MTT and Trypan blue assays. Mode of cell death induced by silibinin was investigated using LDH assay and acridine orange/PI double dye staining. The results showed that silibinin has dose-dependent inhibitory effect on the viability of HepG2 and HUVEC cells. However, Silibinin causes a more continuous dose-dependent cytotoxicity in HepG2 cells compared to the HUVEC cells in which some degrees of resistance is apparent at the beginning. The mode of cell death looks also different in these two cell lines with HepG2 cells being more in favor of apoptosis while necrosis is more evident for the HUVEC cells.