Oxidative stress is a unifying feature of several cardiometabolic risk factors, and has been suggested to be implicated in atherogenesis. This study aimed to investigate the efficacy of supplementation with Heracleum persicum fruit-a common dietary spice-in modulating systemic biomarkers of oxidative stress in subjects undergoing coronary angiography. Twenty-seven subjects with minimal coronary artery disease (CAD; defined as < 50% obstruction in the coronary arteries) were selected for this trial and were randomly allocated to Heracleum persicum hydroalcoholic fruit extract (n = 15; 300 mg/day) or placebo (n = 12) for a period of six months. Patients were visited monthly and asked to report the adverse events during the treatment period. Serum levels of malondialdehyde (MDA), reduced glutathione (GSH) and total antioxidant capacity (TAC), and enzymatic activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) were determined at baseline and at the end of trial. Comparison of changes in the evaluated biomarkers of oxidative stress indicated a significantly greater effect of H. persicum extract versus placebo in reducing serum MDA (p = .001), and elevating GSH (p = .001), and TAC (p = .001) concentrations, as well as activities of GPx (p = .001) and CAT (p = .001). The groups were comparable with respect to changes in serum SOD activities during the course of trial (p = .255). The findings of the present randomized double-blind placebo-controlled trial clearly support the efficacy of H. persicum fruit extract as a safe antioxidant supplement in subjects with minimal CAD.