Mercury (Hg) is a widespread environmental pollutant and toxicant that induces multiple organ damage in humans and animals. Hg toxicity is mediated by the induction of oxidative stress in the target cells. We used uric acid (UA), a potent antioxidant found in biological fluids, to protect human red blood cells (RBC) and lymphocytes against Hg-mediated cell, organelle, and genotoxicity. RBCs were incubated with mercuric chloride (HgCl2), an Hg(II) compound, either alone or in the presence of UA. Incubation of RBCs with only HgCl2 increased the production of nitrogen and oxygen radical species, enhanced methemoglobin levels, heme degradation, free ferrous iron, oxidation of proteins and membrane lipids, and reduced the antioxidant capacity of cells. UA enhanced the antioxidant capacity of RBCs and restored metabolic, plasma membrane-bound, and antioxidant enzyme activities. Scanning electron microscopy showed that UA prevented HgCl2-mediated morphological changes in RBCs. HgCl2 dissipated the mitochondrial membrane potential and increased lysosomal membrane damage in lymphocytes, but UA pre-treatment attenuated these effects. Genotoxicity analysis by comet assay showed that UA protected lymphocyte DNA from HgCl2-induced damage. Importantly, UA itself did not exhibit any deleterious effects on RBCs or lymphocytes. Thus, UA protects human blood cells from Hg(II)-mediated oxidative damage, reducing the harmful effects of this extremely toxic metal. We suggest that UA has a similar protective role in plasma against heavy metal toxicity.