Skin protection against heat shock and the specificity in the organization of antioxidative defenses were examined in rats given oral antioxidative pretreatment with selenium (Se)-enriched yeast and vitamins E, C, and A for 15 days and then exposed to hyperthermia. The activity of antioxidative enzymes in the skin and the liver was monitored 1 hour and 3 hours after heat shock. Glutathione peroxidase (GSH-Px) activity was increased in the skin after heat shock in the groups supplemented with antioxidants, but not in the controls. In contrast, the activity of liver GSH-Px was increased only in the controls receiving antioxidants. Heat shock led to a decrease in liver superoxide dismutase (SOD) activity at 1 hour in the antioxidant-supplemented group, but this was unchanged in the liver of all other groups and in the skin. The activity of thioredoxin reductase (TR) in the skin was increased in the antioxidant supplemented group 1 hour after heat shock, whereas the hepatic thioredoxin reductase activity was decreased. The activities of catalase (CAT), glutathione reductase (GR), and glutathione-S-transferase (GST) were unaffected by either treatment. These results suggest that supplementation with antioxidants protects the skin against heat shock, especially with respect to the GSH-Px and TR activity. The different response of the skin in comparison with the liver probably reflects differences in organization and regulation of antioxidative defenses.