We have shown previously that stilbene estrogen or estrone treatment increases proliferative activity and alters cell cycle. In the present study we present evidence that alterations of the proliferative activity and cell cycle kinetics in the epithelial cells of the manmnmary glands of Noble rats by stilbene estrogen can be significantly blocked by the co-administration with naturally occurring plant flavone, luteolin. Luteolin treatment alone does not have any effect on cell growth, cell proliferation, cell cycle or cell differentiation. Diethylstilbestrol (DES) treatment increased the average number of cells from 3,080 to 8,936 as compared to controls. The average number of cells observed in DES alone treated oup was reduced to 3,845 by luteolin co-treatment. The co-treatment with luteolin significantly reversed the effect of DES on the proliferative activity in all structures of mammary gland. An increase in both labeling index and growth fractions by DES exposure was also significantly reversed by co-treatment with luteolin. Co-treatment with luteolin plus DES led to a 64% decrease in the cells in G1 phase (p < 0.05), whereas cells in S phase were reduced by 55% (p < 0.05) as compared with DES alone. Similarly, the potential doubling time (T(pot)) was significantly reduced from 50-55 h as observed in control group to 22-24 h by DES treatment. However, luteolin co-treatment protected the reduction of (T(pot)) by DES by increasing the potential doubling time from 22-24 h to 33-38 h. Also, co-treatment with luteolin plus DES prevented the conversion of a small percentage of the gland to Lob 2 and Lob 3 compared to DES treated female rats. Antiproliferative action of luteolin suggests that it may have potential anticarcinogenic effects against estrogen-induced mammary carcinogenesis.