Studies were conducted for investigation of the inhibitory effect on the development of experimental tumors of the skin and liver with vitamin A-like compounds, with a particular focus on a new synthetic derivative of the polyprenoic acid 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid (E-5166). Incidence of skin papilloma, chemically induced in mice, was significantly influenced by dietary vitamin A contents. When given orally at a dose of 200 mg/kg body weight, beta-carotene regressed the skin papilloma to some extent (-16% at 14 days), although its effect was much weaker than that of E-5166 (-43%). E-5166 also significantly reduced tumor incidences of experimental hepatomas induced by chemical carcinogen in rats as well as in "spontaneous" hepatoma-bearing mice (C3H/HeNCrj) genetically determined. Further chemical studies revealed that retinol was locally deficient in the hepatomas but not in adjacent normal livers: In particular, anhydroretinol was newly detected in the tumors of spontaneous hepatoma-bearing mice, suggesting increased conversion of retinol into the inactive metabolite. Moreover, cellular retinoid-binding protein, F-type (an oncofetal protein), also newly appeared exclusively in the hepatoma tissues, suggesting that the preventive effect of E-5166 on hepatocarcinogenesis was mediated, at least in part, through its binding with the new retinoid receptor.