d-Penicillamine administered p.o. at a dose of 800 mg/kg, exerts in vivo a stabilizing effect on lysosomal membrane in rat liver. This was demonstrated in normal rats and in the animals whose lysosomes had been rendered fragile by an intraperitoneal injection of 40 mg/kg gamma-HCH. Under these experimental conditions, D-penicillamine protected rat liver against cell necrosis induced by gamma-HCH and prevented, therefore, the efflux β-glycerophosophatase from the organ to the blood plasma. D-Penicillamine also significantly relieved the in vitro labilizing effect of gamma-HCH upon lysosomal membrane in the lysosome-enriched liver suspension. On the other hand. D-penicillamine did not significantly affect the activities of the three acid hydrolases, β-glycerophosphatase β-glucosidase and cathepsin D, chosen as lysosomal marker enzymes, nor their total activities in rat liver. The possible mechanisms by which D-penicillamine exerts protective action on gamma-HCH-induced alterations of rat liver lysosomes are discussed. © 1979.