Red betel vine (Piper crocatum) are commonly used in traditional medicine. Red betel contain flavonoids, alkaloids, tannin, saponin, polyphenolate compounds and atsiri oil. Flavonoids affects neurons through its neuroprotective properties, inducing neuron growth and morphological changes. There are many studies about the benefit of red betel vine. However, the effect of red betel long-term use is needed. Objective : This study is aimed to determine the difference in histopathological findings of the cerebral cortex DDY-strain mice in the exposed to and the group are not exposed to red betel ethanol extract for 90 days. Methods : This experimental study uses a post-test control group design on 60 DDY-strain mice which were divided into four treatment groups and one control group. The treatment groups were given doses of group I 50 mg/kg, group II 100 mg/kg, group III 200 mg/kg, group IV 400 mg/kg and group V received aquadest. Histopathological image was observed into size and amount of pyramidal neurons and thickness of cerebral cortex. Results : There is a significant difference of pyramidal neuron cells amount (p<0.05) between group IV and V, group I and III, group I and IV, and group II and IV. We also found a significant difference of pyramidal neuron cells size (p<0.05) between group III and V, group IV and V, group I and III, group I and IV, and cerebral cortex thickness (p<0.05) between group IV and V, group I and II, group I and III, group I and IV.  Conclusion : There were positive significant difference of histopathological image of the cerebral cortex in DDY-strain mice in the exposed than the group were not exposed to red betel ethanol extract for 90 days. 
Key words : Piper crocatum, cerebral cortex, histopathological image.