We report a novel charge inversion ion/ion reaction that converts multiply charged protein cations to multiply charged protein anions via a single ion/ion collision using highly charged anions derived from nanoelectrospray ionization (nESI) of hyaluronic acids (HAs). This type of charge inversion reaction is demonstrated with cations derived from cytochrome c, apo-myoglobin, and carbonic anhydrase (CA) cations. For example, the reaction has been demonstrated to convert the [CA+22H]22+ carbonic anhydrase cation to a distribution of anions as high in absolute charge as [CA-19H]19-. Ion/ion reactions involving multiply charged ions of opposite polarity have previously been observed to result predominantly in the attachment of the reactant ions. All mechanisms for ion/ion charge inversion involving low energy ions proceed via the formation of a long-lived complex. Factors that underlie the charge inversion of protein cations to high anionic charge states in reaction with HA anions are hypothesized to include: (i) the relatively high charge densities of the HA anions that facilitate the extraction of multiple protons from the protein leading to multiply charged protein anions, (ii) the relatively high sum of absolute charges of the reactants that leads to high initial energies in the ion/ion complex, and (iii) the relatively high charge of the ion/ion complex following the multiple proton transfers that tends to destabilize the complex.