The relation between wine consumption and breast cancer development is a controversial issue. In order to analyze the effect of wine flavonoid components on cell proliferation, several flavonoid-rich fractions with increasing hydrophobicity, were isolated and their effects on the proliferation of a human breast cancer cell line (MCF-7, ER+ve), a non-tumorigenic spontaneously immortalized cell line (MCF-10A) and normal human mammary epithelial cells (HMEC) were studied. A flavonoid fraction that comprised primarily of flavonoid aglycones was the most effective in inhibiting cell proliferation and showed selectivity towards the breast cancer cell line MCF-7. In the presence of this flavonoid fraction, the normal MCF-10A and HMEC cells showed normal growth, whereas the MCF-7 cells underwent a change in morphology into spherical forms. Cytotoxicity analyses suggested that these cells have become apoptotic. The efficiency of inhibition of cell proliferation by various flavonoid fractions appeared to be positively correlated with their inhibition of calcium and calmodulin-promoted phosphodiesterase activity, implicating a potential interference with the calcium second messenger system. The results suggest that grape wine has functional food properties and may be used for disease prevention.