A cone-calix[4]arene derivative, featuring a guanidinium group and a Cu(II) ion ligated to a 1,4,7-triazacyclononane (TACN) ligand at the 1,3-distal positions of the upper rim, effectively catalyzes the cleavage of 2-hydroxypropyl p-nitrophenyl phosphate (HPNP) and a number of diribonucleoside 3',5'-monophosphates (NpN'). Kinetic and potentiometric measurements support the operation of a general-base/general-acid mechanism and demonstrate that the hydroxo form of the ligated Cu(II) ion is the sole catalytically active species. Rate enhancements relative to the background hydrolysis reaction at 1 mM catalyst concentration are 6 × 10(5)-fold for HPNP and cluster around 10(7)-fold with the most favorable catalyst-NpN' combinations.