Red grape seed extract containing proanthocyanidins and other antioxidants are being used as nutritional supplements by many health conscious individuals. The beneficial effects of grape seed proanthocyanidins (GSPE) have been reported, however, little is known about their mechanism(s) of action. One of the beneficial effects of GSPE is chemoprevention of cellular damage. The precise mechanism by which GSPE mediates, chemoprevention is not yet understood. This report addresses this issue. We investigated the mechanisms of actions of GSPE, which ameliorates chemotherapy-induced toxic effects of Idarubicin (Ida) and 4,-hydroxyperoxycyclophosphamide (4-HC) in normal human Chang liver cells. Exposure to GSPE resulted in a significant reduction in apoptosis in response to the cytotoxicity of chemotherapeutic agents. RT-PCR analysis showed a significant increase in the anti-apoptotic gene Bcl-2 and a decrease in the cell cycle associated and proapoptotic genes, c-myc and p53 in cells treated with GSPE. These results suggest that some of the chemopreventive effects of GSPE are mediated by upregulating Bcl-2 and down regulating c-myc and p53 genes.