The aim of our study was to evaluate the effect of a standardized formulation of a polyphenolic extract of grapes (Leucoselect-Phytosome [LP]) on low-density lipoprotein (LDL) susceptibility to oxidation in a group of heavy smokers. A randomized, double-blind, crossover study was undertaken in 24 healthy male heavy smokers, aged > or = 50 years. Enrolled subjects were given 2 capsules twice daily for 4 weeks (phase 1). Each capsule contained 75 mg of a grape procyanidin extracts and soy-phosphatidlcholine or placebo consisiting of 75 mg lactose and soy-phosphatidlcholine. A wash out period of 3 weeks was then followed by 4 weeks of the opposite treatment (phase 2). Blood samples were taken at baseline and at the end of each phase and assayed for plasma lipids and LDL susceptibility to oxidation. Compliance was good, and no adverse effects were recorded. Subjects did not show significant modification of total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C) and LDL-C during LP treatment. Among oxidative indices, thiobarbituric acid reactive substances (TBARS) concentration was significantly reduced in subjects taking LP (-14.7% +/- 21.1% v +5.0% +/- 18.1%, P <.01), and the lag phase prolonged (+15.4% +/- 24.4% v -0.1% +/- 16.0%, P <.05) compared with placebo and basal values. The antioxidant potential of grape seed extract polyphenols may prove effective in a model of oxidative stress (smoking); however more investigational data are needed before use in wider clinical settings.