N-(4-hydroxyphenyl)all-trans-retinamide (4-HPR) has shown cancer chemoprevention activity in many experimental and clinical situations. The purpose of this research is to evaluate the in vivo efficacy of 4-HPR in preventing 7,12-dimethylbenz(alpha)antracene (DMBA)-induced oral carcinogenesis and to study histomorphometric changes. 76 Syrian hamsters were separated into four groups: group 1, untreated controls (16 animals); group 2, 4-HPR controls (16 animals); group 3, DMBA-treated animals (28); group 4, animals treated with DMBA and 4-HPR (16). Hamsters were painted with a 0.5% solution of DMBA three times a week in their left buccal pouch. A diet of 2 mmol of 4-HPR/kg was administered. At week 9, 50% of the animals were killed; the remainder were killed at week 12. Pathology and histomorphometric tests were performed on epithelium, dysplasia and carcinomas. At week 9, 5 carcinomas were found in group 3, and 13 in group 4. Cancers in group 4 were more numerous, endophytic and infiltrating than those in group 3 animals. At week 12, 16 carcinomas were detected in group 3 animals, but group 4 developed more carcinomas per animal than group 3. Using these experimental concentrations, 4-HPR cannot express its best chemopreventive effect.