Background: Coffee is one of the most widely consumed pharmacologically active beverages in the world. Several studies showed that a daily intake of coffee has the protective effect of coronary heart disease, diabetes mellitus, nonalcoholic steatohepatitis and cancer. Recent research suggests that kahweol, a diterpene molecule founded in the coffee bean, has anti-carcinogenic, anti-tumor and anti-inflammatory properties. However, little is known about the anti-tumor mechanisms of kahweol. Here, we examined the anti-tumor effect of kahweol in HepG2 human hepatocellular carcinoma cells. Methods: The effect of kahweol on apoptosis is determined by hoechst and propidium iodide (PI) staining analysis on cultured human hepatocellular carcinoma HepG2 cells. The expression of cleaved caspase-3, cleaved PARP, pAkt, pERK, LC3 and p62 were determined by western blot analysis. To investigate whether kahweol induced apoptosis is related with autophagy, autophagy inhibitor bafilomaycin or autophagy related gene 7 siRNA (SiATG7) were treated. Results: Kahweol increased nuclear condensation and PI staining positive cells and induced cleaved caspase-3 and cleaved PARP expression. In addition, kahweol inhibits insulin induced phosphorylation of Akt , ERK, STAT3. Kahweol also increased expression of LC3-II and p62, indicating inhibition of autophagy. When kahweol was treated with bafilomycin or siATG7, apoptosis was significantly enhanced. Conclusions: This study shows that kahweol increases HepG2 cell apoptosis through caspase 3?dependent pathway and inhibition of autophagy. The present study suggest that kahweol has anti-tumor effect in hepatocellular carcinoma.