Lead-dependent ribozyme (leadzyme) is a ribozyme working with Pb 2 + . In this paper, we have investigated the combined effect of metal ions, especially rare earth ions, on the cleavage reaction by the leadzyme. As a result, it was observed that although only a rare earth ion or another divalent ion except Pb 2 + did not play a role as the catalyst, the addition of a rare earth ion in the presence of Pb 2 + increased significantly the yield of the cleavage reaction. The result suggests that the complex between the leadzyme and the substrate should have two classes of metal ion binding sites.