The fruit bodies of Ganoderma lucidum have been used for the prevention and treatment of various diseases in the Orient. Its antitumor and immune enhancing properties, along with no cytotoxicity, raise the possibility that it could be effective in preventing oxidative damage and resulting disease. Using agarose gel electrophoresis, we have evaluated the potential of Ganoderma lucidum extract as a radioprotector and antioxidant defense against oxygen radical-mediated damage. Although the evidence presented here is based on in vitro using isolated DNA, the results clearly demonstrate that the hot-water extract of Ganoderma lucidum shows good radioprotective ability, as well as protection against DNA damage induced by metal-catalyzed Fenton reactions and UV irradiation. We also found that the water-soluble polysaccharide isolated from the fruit body of Ganoderma lucidum was as effective as the hot-water extract in protecting against hydroxyl radical-induced DNA strand breaks, indicating that the polysaccharide compound is associated with the protective properties. Our data suggest that Ganoderma mushroom merits investigation as a potential preventive agent in humans.