Abstract The role of glucocorticoids and metabolites of hepatic intermediary metabolism as possible mediators of the ethanol-induced stimulation of hepatic phosphatidate phosphohydrolase activity was studied in intact, adrenalectomized, and pyrazole-treated rats. The ethanol-induced increase in the soluble and microsomal phosphatidate phosphohydrolase activity was dependent on the amount of ethanol administered up to a dose of 3 to 4 g/kg body wt, suggesting that the ethanol effect is largely due to an unspecific stress effect of ethanol, and possibly mediated by stress homones such as glucocorticoids. Adrenalectomy abolished the ethanol-induced increase in microsomal phosphatidate phosphohydrolase activity, but did not modify the effect of ethanol on the soluble enzyme. Pyrazole abolished the ethanol-induced increase in soluble phosphatidate phosphohydrolase activity in both intact and adrenalectomized rats, but did not modify the induction of the membrane-bound enzyme in intact rats. The amount of triacylglycerol accumulating in the liver after ethanol administration correlated better with the soluble than with the membrane-bound phosphatidate phosphohydrolase activity. The results suggest that the hepatic phosphatidate phosphohydrolase activities are subject to separate regulatory mechanisms, involving hormones and also low molecular weight metabolites. The soluble and membrane-bound enzymes may have different tasks in hepatic glycerolipid metabolism.