Electrospray ionization (ESI) in the negative ion mode has received less attention in fundamental studies than the positive ion electrospray ionization. In this paper, we study the efficiency of negative ion formation in the ESI source via deprotonation of substituted phenols and benzoic acids and explore correlations of the obtained ionization efficiency values (logIE) with different molecular properties. It is observed that stronger acids (i.e., fully deprotonated in the droplets) yielding anions with highly delocalized charge [quantified by the weighted average positive sigma (WAPS) parameter rooted in the COSMO theory] have higher ionization efficiency and give higher signals in the negative-ion ESI/MS. A linear model was obtained, which equally well describes the logIE of both phenols and benzoic acids (R(2) = 0.83, S = 0.40 log units) and contains only an ionization degree in solution (α) and WAPS as molecular parameters. Both parameters can easily be calculated with the COSMO-RS method. The model was successfully validated using a test set of acids belonging neither to phenols nor to benzoic acids, thereby demonstrating its broad applicability and the universality of the above-described relationships between IE and molecular properties.