Abstract: One of the goals of the study was to investigate the expression pattern of Bmi1 of treated hamsters with piperine after experimentally induced HBP carcinoma. Material and methods: Thirty male Syrian hamsters were randomly split into three groups (G(s)) of ten. Hamsters in groups II and III had 7, 12-dimethylbenz (a) anthracene (DMBA) painted into their right hamster buccal pouch (HBP) three times a week for 14 weeks, whereas hamsters in group I (control) were left untreated for 22 weeks. After that, the animals in GII (positive control) were left with no additional treatment for other 8 ws (total period 22 ws), whereas those in GIII were treated by piperine (50 mg/kg, orally) daily for 4ws, and then, animals were left with no additional treatment for other 4 ws (total period 22 ws). After termination of the experiment, After euthanizing the animals, HBP were surgically removed, cleaned, fixed, and processed for a histological analysis and categorization using H&E stain, and immunohistochemical (IHC) staining utilizing Bmi1 cancer stem cell(CSC) antibody. Results: The gap between GII and GIII was statistically very significant (p value < 0.001) regarding to tumor volume, depth of invasion( DOI) and regarding nuclear expression of Bmi1which revealed that, GI had the smallest average surface area (9.71%), whereas GII had the largest average surface area (65.88%), followed by GIII Conclusions: piperine could inhibit HBP squamous cell carcinoma (SCC) in addition to, downregulation of Bmi1 can predict the therapeutic potential of piperine in HBP SCC.