Cardiovascular disease (CVD) is the leading cause of death in industrialized nations. The initiating event in atherosclerosis, or hardening of the arteries, is oxidation of low density lipoprotein (LDL). Binding with serum albumin and LDL of 41 polyphenols (major antioxidants in plant foods) constituting four classes of flavonoids, three types of phenolic acids,and seven polyphenol conjugate metabolites was investigated indirectly by fluorescence quenching and directly by affinity separation/high-performance liquid chromatography (four of the polyphenols). Stern−Volmer plots yielded K values for the two proteins. Polyphenol binding was significantly stronger for albumin than with LDL. K values were highly correlated with the lipophilicity of the polyphenols. The number of polyphenol molecules determined by quenching was ∼1 for both proteins. Direct analysis under saturation conditions yielded from 2 to 13 molecules of polyphenols/LDL particle. Multiple substituent effects on binding were analyzed. Evidence was put forward that binding of polyphenols to these proteins is protective for CVD by multiple mechanisms.