Red betel vine (Piper crocatum) is one of the plants that are useful to treat some disease. Previous studies concluded that red betel has antimicrobial effect to Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Candida albicans, and also act as breast cancer cell antiproliferation. Some disease require a long-term use of red betel vine to get its benefit. Purposes: The aim of this study is to define the liver histopathological changes in DDY mice due to red betel ethanol extract exposure for 90 days.  Methods: This laboratory experimental study using 43 DDY mice which were divided into four treatment groups and one control group. The treatment groups were given several doses of 50 mg/KgBB, 100 mg/KgBB, 200 mg/KgBB, and 400 mg/KgBB. The control group were given distilled water. Red betel vine extract administered orally. Histopathological changes o the liver are measured using Manja Roenigk scoring methods. Results: There are histopathological changes occured in the group II, III, and IV (p<0.05), whereas there is no histopathological changes in group I compared with control group (p>0.05). Histopathological changes that occur include degeneration cloudy, hydropic degeneration and necrosis. 
Conclusions: Long-term red betel vine ethanol extract exposure at dose 50 mg/KgBB did not change the liver histopathology significantly, while significant histopathological changes occured at dose 100 mg/KgBB, 200 mg/KgBB, dan 400 mg/KgBB. 
Key Words : red betel, sub-chronic toxicity, liver histopathology, scoring hepatocyte Manja Roenigk.