Accumulating evidence suggests that grape seed and wine polyphenol extracts possess a diverse array of actions and may be beneficial in the prevention of inflammatory-mediated disease such as cardiovascular disease and cancer. This study aimed to determine whether the reported pleiotropic effects of several polyphenolic extracts from grape seed products or red wine would also include inhibition of cholesterol uptake and cell proliferation, and inhibit a known specific target of the inflammatory process, that is, 5-lipoxygenase (5-LOX). Incubation of HT29, Caco2, HepG2, or HuTu80 cells in a medium containing [(3)H]cholesterol in the presence of a grape seed extract (GSE) or red wine polyphenolic compounds (RWPCs) inhibited [(3)H]cholesterol uptake by up to 66% (which appeared maximal). The estimated IC(50) values were 60 and 83 microg/mL for RWPC and GSE, respectively. Similar cholesterol uptake inhibitory effects were observed using the fluorescent cholesterol analogue NBD cholesterol. The inhibition of cholesterol uptake was independent of the sample's (GSE and RWPC) potent antioxidative capacity. Red wine polyphenolic compound and GSE dose dependently inhibited HT29 colon adenocarcinoma cell proliferation, which was accompanied by an increase in apoptosis. In addition, RWPC and GSE inhibited 5-LOX activity with the IC(50) values being 35 and 13 microg/mL, respectively. Two of 3 other GSEs tested also significantly inhibited 5-LOX activity. Inhibition of cholesterol uptake and proinflammatory 5-LOX activity may be beneficial in preventing the development of chronic degenerative diseases such as cardiovascular disease and cancer.