The enthalpic and entropic components of Cu2+ and Cu+ binding to the blue copper protein azurin have been quantified with isothermal titration calorimetry (ITC) measurements and analysis, providing the first such experimental values for Cu+ binding to a protein. The high affinity of azurin for Cu2+ is entirely due to a very favorable binding entropy, while its even higher affinity for Cu+ is due to a favorable binding enthalpy and entropy. The binding thermodynamics provide insight into bond enthalpies at the blue copper site and entropic contributions from desolvation and proton displacement. These values were used in thermodynamic cycles to determine the enthalpic and entropic contributions to the free energy of reduction and thus the reduction potential. The reduction thermodynamics obtained with this method are in good agreement with previous results from temperature-dependent electrochemical measurements. The calorimetry method, however, provides new insight into contributions from the initial (oxidized) and final (reduced) states of the reduction. Since ITC measurements quantify the protons that are displaced upon metal binding, the proton transfer that is coupled with electron transfer is also determined with this method. Preliminary results for Cu2+ and Cu+ binding to the Phe114Pro variant of azurin demonstrate the insight about protein tuning of the reduction potential that is provided by the binding thermodynamics of each metal oxidation state.