We have directly measured a 6.6 +/- 0.8 kcal mol(-1) increase in the thermal stability of Saccharomyces cerevisiae iso-1-ferricytochrome c upon reduction of the heme iron at pH 4.6 and 300 K. The stabilization is entirely entropic, contributing 13.2 +/- 6.8 kcal mol(-1) under the above conditions. The dramatic changes in the stability and entropy of denaturation cannot be rationalized in terms of redox-state-dependent changes in structure, mobility, or cross-linking but can be accounted for by redox-state-dependent heme solvation.