The superoxide dismutase mimetic compound, Cu(II) (3,5-diisopropylsalicylate)2 (CuDIPS) inhibited soluble Ca2+/phospholipid dependent protein, kinase (protein kinase C) in rat liver, competing with ATP. The Ca2+/phospholipid- and TPA-stimulated phosphorylation of endogenous proteins were also inhibited by CuDIPS. In vitro and in vivo CuDIPS as well as CuSO4 reduced the activity of TPA-stimulated protein kinase C, while 3,5-diisopropylsalicylate lacked this effect. Our results indicate that CuDIPS interacts with the catalytic domain of the enzyme and the inhibition of protein kinase C may be due to copper(II) ions.