Mercury (Hg) accumulation, transfer, defense mechanism and adverse effects were studied in red deer (Cervus elaphus) and wild boar (Sus scrofa) from the Almadén mining district (Spain), the largest (285,000 t of Hg) and the oldest (more than 2000 years) Hg mine/refining operation site in the world. Red deer (n=168) and wild boar (n=58) liver, kidney, bones (metacarpus), testis and muscle were analyzed for total Hg and selenium (Se) within a range of distances to the Almadén mining district. The highest Hg concentrations were found in kidney (0.092 and 0.103 μg/g d.w. for red deer and wild boar, respectively) followed by the levels in liver (0.013 and 0.023 μg/g d.w. for red deer and wild boar, respectively). A significant correlation (r=-0.609, p=0.007) was found between Hg concentrations and distance to the Almadén Hg mining district. However, both red deer and wild boar closest to the mining area still showed mercury concentrations well below the concentration associated with clinical signs of Hg poisoning. Highest Se concentrations were found in kidney (2.60 and 6.08 μg/g in red deer and wild boar, respectively) and testis (2.20 μg/g in red deer). For selenium, differences between red deer and wild boar were statistically significant (p<0.05) in all tissues, concentrations being higher in wild boar than in red deer. In the diagnosis of Se deficiency, the vast majority of the examined red deer livers were deficient. A significant correlation was found between Hg and Se in kidney (r=0.386, p>0.001 for red deer and r=0.567, p=0.005 for wild boar). Liver GSSG concentrations were negatively correlated to total mercury and Hg:Se molar ratio in male deer, which could indicate a hormetic response to Hg exposure. Moreover, a positive association was found between the antioxidant element Se and antioxidant vitamins in red deer tissues.