Many protein enzymes use general acid-base catalysis as a way to increase reaction rates. The amino acid histidine is optimized for this function because it has a pK _a (whereK _a is the acid dissociation constant) near physiological pH. The RNA enzyme (ribozyme) from hepatitis delta virus catalyzes self-cleavage of a phosphodiester bond. Reactivity-pH profiles in monovalent or divalent cations, as well as distance to the leaving-group oxygen, implicate cytosine 75 (C75) of the ribozyme as the general acid and ribozyme-bound hydrated metal hydroxide as the general base in the self-cleavage reaction. Moreover, C75 has a pK _a perturbed to neutrality, making it “histidine-like.” Anticooperative interaction is observed between protonated C75 and a metal ion, which serves to modulate the pK _a of C75. General acid-base catalysis expands the catalytic repertoire of RNA and may provide improved rate acceleration.