Luteolin and quercetin are widely distributed plant flavonoids that possess a variety of chemical and biological activities, including free-radical scavenging and antioxidant activity. Recently, both flavonoids have been reported to inhibit DNA topoisomerases I and II (topo I and topo II), a property that, together with their ability to induce DNA and chromosome damage, has made them candidate anticancer compounds. In the present study, we confirmed that both compounds are topo II inhibitors by conducting a comparative study of their effect on topo II activity from Chinese hamster ovary AA8 cells. Because interference with the function of topo II to resolve DNA entanglement at the end of replication results in chromosome malsegregation at mitosis, we investigated whether luteolin and quercetin are effective in inducing endoreduplication in AA8 cells. Concentrations of luteolin and quercetin that inhibited topo II catalytic activity resulted in extraordinarily high yields of metaphases showing diplochromosomes. Given the established relationship of polyploidy with tumor development via aneuploidy and genetic instability, these results question the usefulness of luteolin and quercetin in cancer therapy.