Inflammation and oxidative stress — two components of the natural host response to injury — constitute important etiologic factors in the atherosclerotic process. We evaluated whether the norbixin, an unusual dicarboxylic water-soluble carotenoid found in seeds of Bixa orellana L., could reduce the formation of atherosclerotic plaques by mitigating the oxidative stress in aortic tissue and inflammatory events in experimental atherosclerosis. New Zealand rabbits received regular chow or hypercholesterolemic diet alone (regular chow + 0.5% cholesterol) or enriched with BIX 10, 30, or 100 mg/kg for 60 days. This study was approved by the Ethics in Animal Use Committee of the Federal University of Santa Maria (nº 28/2010). The hypercholesterolemic diet increased serum levels of the inflammatory markers TNF-α, IL-1, IL-6, and IF-γ induced lipid and protein oxidation in the aortic tissue and increased the ratio of the intima area to the media area in the aortic arch compared with the control group (538.7 ± 25.6 vs. 45.7 ± 2.8 pg/mL; 279.5 ± 18.7 vs. 28.0 ± 0.9 pg/mL; 419.2 ± 9.7 vs. 38.0 ± 1.9 pg/mL; 350.0 ± 26.2 vs. 34.2 ± 1.3 µg/mL; 0.6 ± 0.01 vs. 0.4 ± 0.02 nmol MDA/mg protein; 4.9 ± 0.3 vs. 3.2 ± 0.2 nmol/mg protein; 0.5 ± 0.03 vs. 0.02 ± 0.00, respectively, p<0.05). Protein oxidation (protein carbonyl groups) change was prevented by all norbixin doses (2.7 – 3.3 nmol/mg protein). However, only 30 and 100 mg/kg of norbixin prevented the histopathological changes and increased levels of lipid oxidation (0.32 - 0.39; 0.43 - 0.49 nmol MDA/mg protein, respectively). Inflammatory markers were not affected by norbixin treatment. Our results support the beneficial role of norbixin in the treatment of atherosclerosis by decreasing oxidative events and preventing the formation of atherosclerotic plaques.