The effect of salicylate, the active metabolite of aspirin (acetyl salicylic acid) in the presence of Ca2+ and phosphate on mitochondrial permeability transition (MPT) was studied. MPT is often associated with opening of a Ca2+ -induced pore. The opening of this pore leads to swelling, loss of mitochondrial membrane potential and release of accumulated Ca2+. In freshly isolated rat kidney mitochondria, salicylate (400 microM) in the presence of 20 nmol Ca2+/mg protein and 0.1 mM phosphate induced swelling, loss of mitochondrial membrane potential and release of accumulated Ca2+. All these changes were eliminated when cyclosporin A (1 microM), (a pore inhibitory agent) was included in the incubation medium. Unlike salicylate, unhydrolyzed aspirin (400 microM) induced these changes slightly. We concluded that salicylate acts as an activator of Ca2+ and phosphate in promoting the opening of kidney inner mitochondrial membrane pore. As a result a great consideration should be given to its toxicological effect.