Liver cells from rats chronically fed a Lieber-De Carli diet for 3 weeks presented a marked decreased in tissue Mg²⁺ content and an inability to extrude Mg²⁺ into the extracellular compartment upon stimulation with catecholamine, isoproterenol or cell permeant cAMP analogs. This defect in Mg²⁺ extrusion was observed in both intact cells and purified liver plasma membrane vesicles. Inhibition of adrenergic- or cAMP-mediated Mg²⁺ extrusion was also observed in freshly isolated hepatocytes from control rats incubated acutely in vitro with varying doses of EtOH for 8 min. In this model, however, the defect in Mg²⁺ extrusion was observed in intact cells but not in plasma membrane vesicles. In the chronic model, upon removal of EtOH from the diet hepatic Mg²⁺ content and extrusion required approximately 10 days to return to normal level both in isolated cells and plasma membrane vesicles. In hepatocytes acutely treated with EtOH for 8 min more than 60 min were necessary for Mg²⁺ content and extrusion to recover and return to the level observed in EtOH-untreated cells. Taken together, these data suggest that in the acute model the defect in Mg²⁺ extrusion is the result of a limited re-filling of the cellular compartment(s) from which Mg²⁺ is mobilized upon adrenergic stimulation rather than a mere defect in adrenergic cellular signaling. The chronic EtOH model, instead, presents a transient but selective defect of the Mg²⁺ extrusion mechanisms in addition to the limited re-filling of the cellular compartments.