Abstract Tert-butyl hydroperoxide (BHP), hydrogen peroxide and diamide caused a rapid and simultaneous release of glutathione disulfide (GSSG) and K + in the isolated perfused rat liver. Both BHP-induced effluxes were suppressed by prior depletion of hepatic glutathione, but not by co-infusion of desferrioxamine which prevented lipid peroxidation and cell death. High K + media decreased the GSSG efflux even though hepatic GSSG levels remained high. The GSSG and K + effluxes were repeatable if cellular K + recovered after a short BHP exposure. Ouabain inhibited the K + re-uptake and decreased the response to repeated BHP challenge. Thus, sinusoidal efflux of GSSG under oxidative stress may be driven by a K + gradient.