The interactions of two trialkyllead (TAL) compounds, (trimethyl)Pb-Cl and (tributyl)Pb-Cl, with mitochodria from rat liver have been studied. A stimulation of the respiratory rate induced by the trialkyllead compounds added at low doses was observed which was not dependent on the presence of chloride in the medium. In contrast with the major current view, we propose that trialkyllead compounds behave as uncouplers of the oxidative phosphorylation and not (or not only) as Cl-/OH- exchangers. In fact the present results suggest that the TAL compounds enter the mitochondria as (alkyl)3Pb+ cations and are extruded as electroneutral (alkyl)3 Pb-OH compounds, the overall result being the transport of a proton through the membrane as in the case of classical uncouplers. The uncoupling effect could explain the toxicity of the compounds as a result of the decrease in the energy level of the cell. Furthermore, such a mechanism, in which the uptake of TAL compounds is supposed to be driven by a negative potential, could explain their preferential toxicity for neuronal cells, which maintain a higher negative-inside potential than most other cell types.