Background: Accumulating evidence suggests that oxidative modification of lipoproteins may play a significant role in atherogenesis. In this study, we hypothesized that the iron chelator deferiprone (L1) would function as an antioxidant and decrease atherosclerosis progression. Materials and Methods: For the in vitro studies, human low-density lipoprotein (LDL) was collected and then subjected to oxidation by either hemin/H2O2 or copper sulfate in the presence of various concentrations of L1. Lag time to oxidation was measured to assess antioxidant activity of L1. In addition, human umbilical vein endothelial cells (HUVEC) were subjected to oxidized LDL in the presence of varying concentrations of L1 to assess the antioxidant cytoprotective ability of L1. For the in vivo studies, rabbits (n = 21) were maintained on a 0.25% by weight cholesterol diet for 10 weeks; 9 rabbits also received twice daily L1 by garage (total dose = 100 mg/kg/day). Lipid profiles were measured during the study. At 10 weeks, rabbits were sacrificed, and thoracic aorta cholesterol content (TACC) and planimetry were determined to assess atherosclerosis severity. Results: In vitro, L1 prevented oxidation of LDL and protected HUVEC from the cytotoxic effects of oxidized LDL in a concentration-dependent manner. In vivo, L1 reduced TACC (P = 0.001), while also significantly decreasing total plasma cholesterol (P = 0.003), very- low-density lipoprotein cholesterol (P = 0.01), and LDL cholesterol (P = 0.002) compared to control Animals. However, no significant differences between L1-treated animals and controls were evident for the surface area of plaque involvement by planimetry (P = 0.3) or in the serum iron levels (P = 0.3). Conclusions: These results confirm that L1 possesses antioxidant activity in vitro and may reduce atherogenesis in vivo.