Litchi fruit pericarp (LFP) extract contains significant amounts of polyphenolic compounds, and exhibits powerful antioxidative activity against fat oxidation in vitro. The purpose of this study is to confirm the anticancer activity of LFP extract against hepatocellular carcinoma in vitro and in vivo, and to elucidate the mechanism of its activity. Human hepatocellular carcinoma cell line was tested in vitro for cytotoxicity, colony formation inhibition, and cell cycle distribution through flow cytometry after treatment with water-soluble crude ethanolic extract (CEE) from LFP. Murine hepatoma bearing-mice were fed doses of 0.15, 0.3, and 0.6 g/kg/day of water-soluble CEE in DH2O p.o. for 10 days, respectively, to test the anticancer activity and BrdU incorporation of cancer cells in vivo. LFP extract demonstrated a dose- and time-dependent inhibitory effect on cancer cell growth; IC50 was 80 mg/ml, and significantly inhibited colony formation in vitro, tumor growth and BrdU incorporation into cancer cells in vivo. The tumor inhibitory rates at doses of 0.15, 0.3, and 0.6 g/kg/day were 17.31% (PO0.05), 30.77% (P!0.05), and 44.23% (P!0.01), respectively. BrdU labeled tumor cells of treated animals were 11.80G2.79%, and were significantly lower than that in untreated controls (23.00G5.42%, P!0.05). Our findings showed that LFP extract exhibited potential anticancer activity against hepatocellular carcinoma in vitro and in vivo through proliferating inhibition and apoptosis induction of cancer cells.