Abstract: Objective To explore the effect and mechanism of feverfew lactone on inducing autophagic death of hepatocellular carcinoma. Methods The proliferation of hepatocellular carcinoma SMMC 7721 cells treated with feverfew lactone was measured by MTT assay. The autophagy of SMMC 7721 induced with feverfew lactone was assessed by acridine orange staining, autophagic marker LC3 and p62 detecting and autophagic flows analyzing. In addition, a role of ROS in this process was stated by treatment with antioxidant agent N-acetyl-L-cysteine (NAC). Results The proliferation of SMMC 7721 cells were inhibited by feverfew lactone in a concentration dependence manner. The expression of LC3 and autophagic flows of SMMC 7721 cells were increased by feverfew lactone, while p62 was decreased, which implied that feverfew lactone could induce the autophagy of SMMC 7721 cells. Further more, the autophagy effect induced by feverfew lactone was declined obviously when traeted with NAC suggested that ROS played an important role in this effect. Conclusion Feverfew lactone induces autophagic death of SMMC 7721 cells by stimulating cells to produce ROS. The study will be helpful for the treatment of hepatocellular carcinoma and to provide theoretical basis for the clinical application of feverfew lactone.