The effect of 4,4'-bis(beta-diethylaminoethoxy)alpha,beta-diethyldiphenylethane (DH) on lipid metabolism in the liver differed considerably in different animal species, humans, monkeys, and rats, because of differences in drug-metabolizing ability. Monkeys retain considerable drug-metabolizing ability as compared with humans, but the DH-hydroxylating activity in monkeys seems to be much lower than in rats. The hydroxyl derivative was the major substance which accumulated in rat liver following the administration of DH, while DH itself and its N-dealkylated substances accumulated in monkey liver. N-Dealkylated substances were also observed in human liver, but the amount was much smaller than in monkeys. Bis(monoacylglyceryl)phosphate (BMGP), which is characteristic of this kind of drug-induced lipidosis, did not increase as much in monkey liver as in human liver, but a marked increase in phosphatidyl inositol (PI) was observed in monkey liver during administration of DH. The concentration of acidic phospholipids (BMGP + PI) in liver showed a close correlation with the accumulation of the drug (DH + its metabolites), irrespective of species differences. Among subcellular particles isolated from a monkey liver following administration of DH, the crude mitochondrial fraction, including lysosomes, was richest in BMGP.