Recent studies reported that dilazep, which is used clinically as a coronary vasodilator and an antiplatelet agent, attenuates cellular injury induced by hydrogen peroxide, indicating that dilazep possesses free radical-scavenging action. We studied the effect of dilazep on oxidative modification of low density lipoprotein (LDL) promoted by copper ions and THP-1 macrophage (Mφ). In these oxidation systems, the extent of lipid peroxidation of LDL was determined by measuring the formation of conjugated dienes, the formation of thiobarbituric acid-reacting substances (TBARS), and the agarose gel electrophoretic mobility of LDL. When LDL (100 μg protein/ml) was incubated with 1.66 μM Cu 2 + in phosphate buffered saline at 37°C for 3 h, dilazep increased the lag time of the formation of conjugated dienes during Cu 2 + -mediated oxidation of LDL, and inhibited both the formation of TBARS and the increase of electrophoretic mobility of LDL in a dose-dependent manner. At a concentration of 1 mM, dilazep achieved 92% inhibition of Cu 2 + -mediated formation of TBARS. Dilazep (100 μM) decreased the electrophoretic mobility of LDL by 80%, relative to Cu 2 + -modified LDL. Furthermore, when LDL (100 μg protein/ml) was incubated with THP-1 Mφ in Ham's F-10 medium at 37°C for 24 h, the formation of TBARS in the medium was inhibited by dilazep in a dose-dependent manner. Incubation of LDL with THP-1 Mφ in the absence of dilazep yielded 39.8 nmol MDA/mg LDL protein as TBARS, whereas the addition of 50 μM dilazep resulted in an inhibition of the formation of TBARS by 33% and a decrease of the electrophoretic mobility of Mφ-modified LDL. These data indicate that dilazep has the potent effect of protecting LDL from oxidation mediated by copper ions and THP-1 Mφ, and may be clinically used as an antioxidant drug to inhibit the development of atherosclerosis.