Abstract Background The antioxidant AGI-1067 was shown to reduce experimental atherosclerosis. The present study originally intended to study restenosis as a primary endpoint but was subsequently modified to primarily investigate the effects of AGI-1067 on coronary atherosclerosis. Methods and results This placebo-controlled randomized trial assessed the effects of AGI-1067 280 mg qd started before percutaneous coronary intervention (PCI) and administered for 12 months after PCI on atherosclerosis progression as assessed by coronary intravascular ultrasound (IVUS). Among patients with IVUS examinations considered technically adequate both at baseline and follow-up upon central laboratory assessments ( n = 232), plaque volume was not significantly modified with placebo (least squares mean change: −0.4 mm3 , P = 0.85 versus baseline), but was significantly reduced by −4.0 mm3 at end of treatment in the AGI-1067 group ( P = 0.001 versus baseline, P = 0.12 versus placebo). LDL-cholesterol varied by −9% and +4% in the placebo and AGI-1067 groups, respectively ( P < 0.05 between groups), and HDL-cholesterol was reduced by 1% with placebo and 14% with AGI-1067 ( P < 0.05 between groups). Plasma myeloperoxidase was reduced by 6% with AGI-1067 ( P < 0.05) but hs-CRP was not significantly different between groups. Conclusions Atherosclerosis regression (−4.0 mm3 ) was observed in patients treated with AGI-1067, although this was not significantly different from placebo. The anti-inflammatory effect of AGI-1067 is supported by reduced levels of myeloperoxidase.