The pK(a) values of Lys-66, Glu-66, and Asp-66 buried in the interior of the staphylococcal nuclease Delta+PHS variant were reported to be shifted by as much as 5 pKa units from their normal values. Reproducing the pK(a) of these buried ionizable residues using continuum electrostatic calculations required the use of a high protein dielectric constant of 10 or higher. The apparent high dielectric constant has been rationalized as a consequence of a local structural reorganization or increased fluctuations in the microenvironment of the mutation site (Chimenti, M. S., et al. J. Mol. Biol. 2011, 405, 361-377). We have calculated the dielectric constant of A+PHS and the Lys-66, Asp-66, and Glu-66 mutants from first principles using the Kirkwood-Frohlich equation and discovered that staphylococcal nuclease has a naturally high dielectric constant ranging from 20 to 30. This high dielectric constant does not change significantly with the mutation of residue 66 or with the ionization of the mutated residues. Calculation of the spatial dependence of the dielectric constant for the microenvironment of residue66 produces a value of about 10, which matches well with the apparent dielectric constant needed to reproduce pKa values from continuum electrostatic calculations. Our results suggest an alternative explanation that the high dielectric constant of staphylococcal nuclease is a property resulting from the intrinsic backbone fluctuations originating from its structural architecture.