Epidemiological studies demonstrated that human exposure to methylmercury (MeHg) may contribute to the development and progression of metabolic and cardiovascular disorders. However, the mechanisms involved and the role of selenium (Se) and vitamin E (V(E)) supplementation in modulating MeHg cardiovascular toxicities remain unclear. This study examined the effects of Se and V(E) supplementation on MeHg-mediated systemic oxidative stress, antioxidant defense, inflammation, and endothelial dysfunction in an animal model. Male Sprague-Dawley rats were fed a starch-based casein diet or the same diet supplemented with 1 or 3 mg Se/kg diet and with or without 250 or 750 mg V(E)/kg diet. After 28 days of dietary treatment, rats were gavaged with 0 or 3 mg MeHg/kg BW for 14 consecutive days. Results suggested that exposure to MeHg may increase the risk of cardiovascular disease by decreasing circulating paraoxonase-1 activities, increasing serum oxidized low density lipoprotein levels, and associated systemic inflammation and endothelial dysfunction as reflected by increased leukocyte counts and serum levels of intercellular adhesion molecule-1 and monocyte chemotactic protein-1. Se and V(E) supplementation may either alleviate or augment the effects of MeHg, depending on their doses and combinations.