The accumulation of Ca 2 + by rat liver mitochondria in the presence of P i results in spontaneous activation of respiration, accompanied by progressive loss of the accumulated cation. The lipid peroxidation inhibitor, butylated hydroxytoluene, completely prevents and reverses the loss of accumulated Ca 2 + and restores respiration to the state 4 level, but exerts no effect on the rate of Ca 2 + accumulation and respiration in the presence of the uncoupler. The strong inhibition by butylated hydroxytoluene of ruthenium red-insensitive Ca 2 + efflux has also been observed. No correlation between the BHT-sensitive Ca 2 + loss and the formation of malonic dialdehyde in mitochondria has been found. The data obtained suggest that the Ca 2 + -induced uncoupling of mitochondria is mainly due to the appearance of electrogenic ion fluxes that are controlled by the initial steps of lipid peroxidation.