The hepatitis delta virus (HDV) ribozyme uses the nucleobase C75 and a hydrated Mg2+ ion as the general acid-base catalysts in phosphodiester bond cleavage at physiological salt. A mechanistic framework has been advanced that involves one Mg2+-independent and two Mg2+-dependent channels. The rate-pH profile for wild-type (WT) ribozyme in the Mg2+-free channel is inverted relative to the fully Mg2+-dependent channel, with each having a near-neutral pK(a). Inversion of the rate-pH profile was used as the crux of a mechanistic argument that C75 serves as general acid both in the presence and absence of Mg2+. However, subsequent studies on a double mutant (DM) ribozyme suggested that the pK(a) observed for WT in the absence of Mg2+ arises from ionization of C41, a structural nucleobase. To investigate this further, we acquired rate-pH/pD profiles and proton inventories for WT and DM in the absence of Mg2+. Corrections were made for effects of ionic strength on hydrogen ion activity and pH meter readings. Results are accommodated by a model wherein the Mg2+-free pKa observed for WT arises from ionization of C75, and DM reactivity is compromised by protonation of C41. The Bronsted base appears to be water or hydroxide ion depending on pH. The observed pK(a)'s are related to salt-dependent pH titrations of a model oligonucleotide, as well as electrostatic calculations, which support the local environment for C75 in the absence of Mg2+ being similar to that in the presence of Mg2+ and impervious to bulk ions. Accordingly, the catalytic role of C75 as the general acid does not appear to depend on divalent ions or the identity of the Bronsted base.