In the presence of the uncoupler, external zinc ions inhibit rapidly turnover of cytochrome c oxidase reconstituted in phospholipid vesicles or bound to the membrane of intact mitochondria. The effect is promoted by electron leaks into the oxidase during preincubation with Zn 2+ . Inhibition of liposomebound bovine cytochrome oxidase by external Zn 2+ titrates with a K i of 1 ± 0.3 lM. Presumably, the Zn 2+ -binding group at the positively charged side is not reactive in the oxidized enzyme, but becomes accessible to the cation in some partially reduced state(s) of the oxidase; reduction of Cu B is tentatively proposed to be responsible for the effect.