The chemopreventive effect of dietary administration of a new arotinoid, mofarotene (Ro 40-8757), which contains a morpholine structure in the polar end group, during the initiation phase of 4-nitroquinoline 1-oxide (4-NQO)-induced oral carcinogenesis was investigated in male F344 rats. Also, modulatory effects of this compound on polyamine levels (biomarkers of proliferation), the 5-bromodeoxyuridine-labeling index and the number of silver stained nucleolar organizer region proteins (AgNORs)/nucleus were assessed in the target epithelium. Rats were fed Ro 40-8757 at concentrations of 250 and 500 p.p.m. for 10 weeks. One week after the commencement of the diets, 4-NQO (20 p.p.m.) was administered in the drinking water for 8 weeks. Feeding of Ro 40-8757 at both doses caused a 78% reduction in the incidence of tongue neoplasms (squamous cell papilloma and carcinoma) by 32 weeks when compared with rats treated with 4-NQO alone (P < 0.05). Similarly, in rats treated with 4-NQO together with Ro 40-8757 the incidence of preneoplastic lesions (hyperplasia and dysplasia) was significantly less than the 4-NQO alone group (P < 0.05). Expression of three biomarkers was also decreased significantly by dietary treatment with Ro 40-8757. Thus a new arotinoid, Ro 40-8757, inhibited the oral carcinogenesis induced by 4-NQO when it was administered concurrently with the carcinogen. These results might suggest the possible application of Ro 40-8757 for cancer chemoprevention in the oral cavity, in addition to the breast.