Fluorosis is a serious public health problem in many parts of the world where drinking water contains more than 1 ppm of fluoride. The main manifestations of skeletal fluorosis are crippling bone deformities, spinal compressions, and restricted movements of joints. Although fluorosis is irreversible, it could be prevented by appropriate and timely intervention through understanding the process at biochemical and molecular levels. As in the case of many chronic degenerative diseases, increased production of reactive oxygen species (ROS) and lipid peroxidation has been considered to play an important role, even in the pathogenesis of chronic fluoride toxicity. However, there is inconclusive proof for an altered oxidative stress and antioxidant balance in fluorosis, and the existing data are not only conflicting but also contradictory. In the present communication we have evaluated the antioxidant defense system (both enzymatic and nonenzymatic) and lipid peroxidation in both humans from an endemic fluorosis area (5 ppm fluoride in the drinking water) and in rabbits receiving water with 150 ppm of fluoride for six months. There was no significant difference in lipid peroxidation, glutathione, and vitamin C in the blood of human fluorotic patients and fluoride-intoxicated rabbits as compared to respective controls. Neither were there any changes in the activities of catalase, superoxide dismutase, glutathione peroxidase, or glutathione S-transferase in the blood due to fluoride intoxication (of rabbits) or fluorosis in humans. The results together do not subscribe to oxidative stress theory in fluorosis. Thus, in the absence of clear proof of oxidative damage and to counter toxic effects of fluoride through supplementation of antioxidants, extensive investigations are needed to conclusively prove the role of oxidative stress in skeletal fluorosis.