We compared the changes in tissue aerobic metabolism and oxidative damage elicited by hypothyroid rat treatment with T3 and its analog GC-1. Aerobic capacities, evaluated by cytochrome oxidase activities, were increased more by T3 than by GC-1. Furthermore, the response of the tissues to T3 was similar, whereas the response to GC-1 was high in liver, low in muscle and scarce in heart. Both treatments induced increases in ADP-stimulated O2 consumption, which were consistent with those in aerobic capacities. However, unlike T3, GC-1 differentially affected pyruvate/malate- and succinate-supported respiration, suggesting that respiratory chain components do not respond as a unit to GC-1 stimulation. According to the positive relationship between electron carrier levels and rates of mitochondrial generation of oxidative species, the most extensive damage to lipids and proteins was found in T3-treated rats. Examination of antioxidant enzyme activities and scavenger levels did not clarify whether oxidative damage extent also depended on different antioxidant system effectiveness. Conversely, the analysis of parameters determining tissue susceptibility to oxidants showed that pro-oxidant capacity was lower in GC-1- than in T3-treated rats, while antioxidant capacity was similar in treatment groups. Interestingly, both agonists decreased serum cholesterol levels, but only GC-1 restored euthyroid values of heart rate and indices of tissue oxidative damage, indicating that GC-1 is able to lower cholesterolemia, bypassing detrimental effects of T3.