The effects of diltiazem on oxygen uptake, glucose release, lactate production and pyruvate production in the perfused liver from fed rats were investigated. Diltiazem inhibits oxygen uptake and glycolysis. Glucose release from endogenous glycogen is increased after cessation of diltiazem infusion. The reversion of the inhibitory effects of diltiazem after cessation of infusion takes place very slowly. The compound also abolishes glucose release activation by norepinephrine, methotrexate and atractyloside. These effects seem to be the consequence of a more general effect of the drug on metabolism. It can be concluded that 0.5 mM diltiazem is highly toxic to the liver and that it should not be considered a specific agent against Ca(2+)-dependent hormones.