The reduction potentials (E-0) of type 1 (T1) or blue copper (BC) sites in proteins and enzymes with identical first coordination spheres around the redox active copper ion can vary by similar to 400 mV. Here, we use a combination of low-temperature electronic absorption and magnetic circular dichroism, electron paramagnetic resonance, resonance Raman, and S K-edge X-ray absorption spectroscopies to investigate a series of second-sphere variants-F114P, N47S, and F114N in Pseudomonas aeruginosa azurin-which modulate hydrogen bonding to and protein-derived dipoles nearby the Cu-S(Cys) bond. Density functional theory calculations correlated to the experimental data allow for the fractionation of the contributions to tuning E-0 into covalent and nonlocal electrostatic components. These are found to be significant, comparable in magnitude, and additive for active H-bonds, while passive H-bonds are mostly nonlocal electrostatic in nature. For dipoles, these terms can be additive to or oppose one another. This study provides a methodology for uncoupling covalency from nonlocal electrostatics, which, when coupled to X-ray crystallographic data, distinguishes specific local interactions from more long-range protein/active interactions, while affording further insight into the second-sphere mechanisms available to the protein to tune the E-0 of electron-transfer sites in biology.