We studied the effect of a combination of vitamin E, vitamin C, and beta-carotene on the susceptibility of LDL to oxidation, as determined by lag phase (minutes), in a 12 week clinical trial of 45 patients with coronary artery disease (CAD), mean age 60.6 +/- 8.6 years. Subjects were randomized to one of the following interventions (15 each): 1) placebo; 2) vitamin E 400 IU, vitamin C 500 mg, beta-carotene 12 mg (mid dose); or 3) vitamin E 800 IU, vitamin C 1000 mg, beta-carotene 24 mg (high dose). Two baseline, one 6 week and two 12 week measurements of standard lipoproteins and lag phase (Lag) were obtained. Compared to baseline, 12 week plasma concentrations of alpha-tocopherol increased 2 and 3 fold; vitamin C increased 1.5 and 2 fold; and beta-carotene increased 6 and 10 fold in the mid and high dose groups respectively with no change in the placebo group. Lag significantly increased from baseline (190.1 +/- 63.8) to 12 weeks (391.1 +/- 153.0) in the high dose group (p < 0.01). No significant within group change for Lag was observed for the placebo or mid dose group at 12 weeks. A significant between group difference in Lag was observed at 12 weeks, attributable to high dose vs. placebo (p < 0.05). Results were not altered by adjusting for age, sex or other significant clinical predictors of lag phase. We conclude supplementation with a combination of antioxidant vitamins reduces the susceptibility of LDL to oxidation in patients with CAD. These results may be significant for the secondary prevention of CAD.