Epidemiological studies suggest that the consumption of red wine lowers the risk of cardiovascular disease. Although the cardioprotective effect of red wine has been attributed to its polyphenolic content, presently, very little is known about the mechanisms by which these compounds benefit the cardiovascular system. Therefore, the aim of this study was to elucidate whether red wine polyphenolics attenuate the synthesis and secretion of proatherogenic chylomicrons from intestinal cells. Apolipoprotein B48 levels (marker of intestinal chylomicrons), quantitated by western blotting, were significantly reduced by 30% in cultured CaCo-2 cells and medium when cells were incubated with either dealcoholized red wine, alcoholized red wine, or atorvastatin compared with controls. Intracellular cholesterol availability was also attenuated in cells incubated with dealcoholized red wine (72.5%), alcoholized red wine (81.5%), and atorvastatin (83.5%) compared to control cells. Collectively, this study suggests that red wine polyphenolics downregulate the production of atherogenic chylomicrons from intestinal cells, which may explain the reduced CVD mortality rates following its consumption.