The protective effect of cyclosporin A on the damage induced by Hg2+ in kidney mitochondria was studied. Cyclosporin, added in vitro at a concentration of 0.5 microM, reversed the deleterious effects of Hg2+ on transmembrane potential and Ca2+ accumulation. However, when injected in rats, together with Hg2+, cyclosporin failed to protect against Hg2+ poisoning. Due to the low activity of cyclophilin found in kidney mitchondria, it is proposed that the protection of cyclosporin in vitro must be exerted through an independent mechanism different from its binding to cyclophilin.