1. The non-steroidal anti-inflammatory naproxen inhibited steady-state glycogenolysis stimulation caused by norepinephrine, phenylephrine (alpha 1-agonists) and methotrexate (not receptor mediated) in the isolated perfused rat liver. Stimulation of glycogenolysis caused by these agents is Ca(2+)-dependent. 2. Naproxen did not inhibit glycogenolysis stimulation caused by glucagon. 3. The action of naproxen depended on the extracellular Ca2+ concentration. At 0.25 mM extracellular Ca2+, the norepinephrine stimulated glycogenolysis was inhibited by 60% by 0.5 mM naproxen. At 3.5 mM Ca2+, inhibition was reduced to 25%. The inhibition degree correlated linearly with the extracellular Ca2+ concentration. 4. 45Ca2+ efflux stimulation caused by norepinephrine was not affected by naproxen, indicating that the mobilization of the intracellular Ca2+ pools was not significantly affected by naproxen. The initial increases in glycogenolysis caused by norepinephrine in the absence of extracellular Ca2+ (pre steady-state) were not affected by naproxen. These increases depend on intracellular Ca2+ mobilization. 5. It can be concluded that the action of naproxen is most probably related to the cytosolic Ca2+ concentration which, under steady-state conditions, depends on the extracellular one during the action of Ca(2+)-dependent glycogenolytic agents.