In the present study, the effects of thymosin alpha(1) on lipid peroxidation were studied in an in vivo model of experimental hypercholesterolemia. In groups II-IV, rabbits were fed a high-cholesterol diet 2% (w/w) for 10 weeks. Thereafter, rabbits in group III were fed a normal diet for another 14 days and those in group IV were given a normal diet plus 25 mu g/kg thymosin alpha(1) intraperitoneally every other day for the same period. At the end of this period, plasma and erythrocyte lipid levels and susceptibility of erythrocytes to lipid peroxidation were determined in all groups. Hypercholesterolemic rabbits had high plasma and erythrocyte lipid peroxide (TBARS) levels compared to control animals fed a normal diet. Plasma and erythrocyte TEARS levels significantly decreased in the thymosin-alpha 1-injected rabbits. In thymosin-alpha(1)-treated animals (group IV), most of the lipid plaques were replaced by fibrous tissue. These findings suggest that thymosin alpha(1) may have some beneficial effects on the treatment of atherosclerosis by normalizing blood lipid levels and by substantially protecting endothelial cells against free radical injury.