The buccal mucosa is the site at highest risk of contracting malignancy in habitual betel-quid chewers who expose the buccal mucosa to high doses of carcinogens. Of all oral squamous cell carcinomas (SCCs), those of the buccal mucosa are most associated with the poorest prognoses. Therefore, an animal model would be helpful to evaluate new treatment modalities for buccal SCC. We evaluated whether the VX2 rabbit cancer model could be employed as a cancer model for human buccal SCC. Ten adult male, New Zealand White outbred rabbits were randomly divided into two groups A (n=2) and B (n=8). A 0.5 ml VX2 tumor cell suspension containing approximately 40 x 10(6) vital cells was injected intramuscularly into the right hind paw of the two rabbits of group A. Four weeks later, moderately to poorly differentiated hind paw SCCs were apparent in both rabbits of group A. No abdominal organ metastases, but multiple pulmonary metastases, were found in both animals. Fresh solid tumor pieces (about 5 x 5 mm) obtained from group A animals were subsequently inserted into the surgically created spaces of the left cheeks of the eight rabbits of group B. Ulcerated buccal tumors (moderately to poorly differentiated SCCs) were found in all eight animals 6 weeks later. No internal organ metastases were noted in any of the eight rabbits, but a total of 11 with an average of 2.75 cervical lymph node metastases were found in four of the eight animals. Mandibular bone and tooth pulp invasion by cancer cells was also noted in one animal. In conclusion, our findings indicated that VX2-induced rabbit buccal carcinomas could be a potential cancer model for human buccal mucosa squamous cell carcinoma.