The hemodynamic effects of diltiazem in the liver are strictly Ca2+ -dependent Consequently, Ca2+ -free perfusion can be used for investigating the metabolic effects of diltiazem without interference by hemodynamics. Livers were perfused with Krebs/Henseleit-bicarbonate buffer (pH 7.4). For performing Ca2+ -free perfusion the cation was omitted from the perfusion fluid and the cellular pools were exhausted by repeated phenylephrine infusions. Three conditions were investigated with and without Ca2+ : (1) substrate-free perfusion fluid; (2) 0.3 mM [1-(14)C]octanoate infusion; (3) 0.3 mM [1-(14)C]palmitate infusion. The following results were obtained: 1. Oxygen uptake stimulation caused by octanoate and palmitate was abolished by 500 microM diltiazem in the presence of Ca2+; in the absence of Ca2+ there was no inhibition (octanoate) or it was much smaller (palmitate); 2. The 14CO2 production was inhibited in the presence of Ca2+; in the absence of Ca2+ there was no inhibition (palmitate) or even stimulation (octanoate). 3. Ketogenesis from endogenous sources, from palmitate and from octanoate was inhibited by diltiazem in the presence as well as in the absence of Ca2+. The beta-hidroxybutyrate/acetoacetate ratio was diminished in the presence and in the absence of Ca2+ . It was concluded that inhibition of fatty acid oxidation by diltiazem depends partly on the Ca2+ -dependent hemodynamic effects and partly on a Ca2+ -independent action on some enzymatic system.