The modifying effects of dietary exposure of three flavonoids, chalcone, 2-hydroxychalcone, and quercetin, during the initiation and postinitiation phases of oral tumorigenesis initiated with 4-nitroquinoline-1-oxide (4-NQO) were investigated in male F344 rats. At 6 weeks of age, animals were divided into experimental and control groups. At 7 weeks of age, all animals except those treated with test chemicals alone and the untreated control group were given 4-NQO [20 parts/million (ppm)] in the drinking water for 8 weeks to induce oral neoplasms. For chemopreventive study by feeding of test compounds during the initiation phase, groups of animals were given diets containing 500 ppm chalcone, 500 ppm 2-hydroxychalcone, or 500 ppm quercetin for 10 weeks, starting 1 week before 4-NQO exposure. Seven days after stopping 4-NQO exposure, these groups were switched to the basal diet and kept on this diet until the end of the experiment. For chemopreventive study by treatment with test chemicals during the postinitiation phase, starting 1 week after the cessation of 4-NQO administration, the groups given 4-NQO and the basal diet were switched to the diets mixed with test chemicals and maintained on these diets for 22 weeks. The other groups consisted of rats fed diets containing 500 ppm test chemicals alone or of untreated rats. Thirty-two weeks after the start of the study, the incidence of tongue neoplasms and preneoplastic lesions, polyamine levels in the tongue epithelium, and cell proliferation activity estimated by bromodeoxyuridine labeling index were compared among the different dietary groups. Feeding of all test chemicals during either initiation or postinitiation phases caused a significant reduction in the frequency of tongue carcinoma (68-88% reduction; P < 0.05). Dietary administration of these test chemicals also significantly decreased the bromodeoxyuridine labeling index of the tongue squamous epithelium (P < 0.05). In addition, polyamine levels in the oral mucosa were lowered in rats treated with 4-NQO and test chemicals when compared to those given 4-NQO alone. These results indicate that the flavonoids chalcone, 2-hydroxychalcone, and quercetin present in our daily foods have an inhibitory effect on oral carcinogenesis initiated with 4-NQO, and such a modifying effect may be related partly to the suppression of cell proliferation.