Objective:To observe the effects of Akebia Fruit seed (AFS) extract on morphology of different hepatocellular carcinoma cells. Methods By the comprehensive application of cell biology, scanning electron microscopy(SEM) and transmission electron microscopy(TEM),the effects of alcohol extract of AFS on the morphological characteristics of HepG2, Huh 7, and SMMC7721 were observed.  Results: Untreated HepG2 cells show overlapping growth and the surfaces are fully covered with villus. After the treatment with AFS extract, the partial cell villus atrophied and disappeared, the cells became irregular and even collapsed, and rough endoplasmic reticulum(ER) expanded to different degrees. Spontaneous apoptosis could form in Huh 7 cells. After the treatment with AFS extract, the irregular villus, cell shrinking, a lot of apoptotic bodies, and numerous vacuoles caused by endoplasmic reticulum stress were observed in cells. Untreated SMMC-7721 cells are fully covered with longer villus. After the treatment with AFS extract, abnormal morphology could be detected. The cell body expansion with irregular round shape were observed,some regions on the surface of cells collapsed or upheaved,the surface of some cells collapsed due to severe endoplasmic reticulum stress, and a large number of heavily expanded endoplasmic reticulum were commonly found.  Conclusion: These three kinds of hepatocellular carcinoma cell lines exhibit various morphological characteristics, but serious ER stress with different degrees can be induced after the treatment with Akebia Fruit seed extract,which may be one way of Akebia Fruit seed acting on liver cancer.