Recent studies have suggested that ibuprofen inhibits low-density lipoprotein oxidation in a high dose-dependent manner and is a promising drug for treatment of the conditions associated with atherosclerosis. In this article, we present the NMR spectroscopic evidence for the interaction between ibuprofen and phospholipids in lipoprotein particles in intact human plasma. Ibuprofen caused chemical shift upfield drifts for the protons of -N(+)(CH(3))(3) moieties of phosphatidylcholine and sphingomyelin, olefinic chains (-CH[double bond]CH[bond], [bond]CH[triple bond]CHCH(2)CH[triple bond]CH[bond], [bond](CH(2))(n)CH(2)CH[double bond]), and (CH(2))(n) and CH(3) groups, from unsaturated lipids in lipoprotein particles. The ibuprofen may interact directly with the above-mentioned groups of phospholipids or induce structural changes in the lipoproteins. This may shed light on the mechanism by which the drug protects against oxidative modification of lipoproteins.