Abstract: This study aimed to investigate the expression pattern of Bmi1 of treated hamsters with imiquimod and piperine either alone or in combination with each other, after experimentally induced HBP carcinoma. Material and methods: 50 Syrian male hamsters were divided into 5 equal group(s) (G(s)), 10 each. The animals in GI were left untreated for 22 weeks (ws), while the right hamster buccal pouch (HBP) of those in (GII, GIII, GIV and GV) were painted with 7, 12-dimethylbenz (a) anthracene (DMBA), three times a week for 14 ws. 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 painted with imiquimod three times a week for other 4 ws, while those in GIV were treated by piperine (50 mg/kg, orally) daily for 4ws, and those in GV painted with imiquimod three times a week and in the same time were given piperine (50 mg/kg, orally) daily for 4ws then, (GIII, GIV and GV) were left with no additional treatment for other 4 ws (total period 22 ws). After termination of the experiment, the animals were euthanized, and all right HBP were surgically excised, prepared, fixed and processed for hematoxylin and eosin (H&E) stain examination for histological examination and classification, and immunohistochemical (IHC) staining utilizing B-lymphoma moloney murine insertion region (Bmi1) cancer stem cell(CSC) antibody. Results: There was a high significant difference between GII and the treated Gs (GIII, GIV& GV) (p value < 0.001) regarding to tumor volume, depth of invasion( DOI) and regarding nuclear expression of Bmi1which revealed that, GI had recorded the lowest mean area percentage (9.71%), while GII had recorded the highest mean area percentage (65.88 %),followed by GIII and then GIV Conclusions: imiquimod and piperine could inhibit HBP squamous cell carcinoma (SCC) formation either alone or in combination with each other, in addition to downregulation of Bmi1 can predict the therapeutic potential of imiquimod and piperine in HBP SCC.