The rate and mechanism of the kinetic energy relaxation of directly excited heme in cytochrome c was investigated using classical molecular dynamics simulation. The kinetic energy relaxation was found to be a biphasic exponential decay process with relaxation time constants of 1.5 ps for the fast process and 10.1 ps for the slow process. Approximately 60% of the kinetic energy relaxes on the short time scale. Energy flow from the heme to the protein is found to occur "through bond" via (1) covalent linkages of the heme to the Cys14, Cys17, His18, and Met80 protein residues and (2) hydrogen bonds to Tyr48, Thr49, Asn52, and Thr-78 protein residues and nearby water molecules and "through space" via nonbonded collisional energy transfer to nearby heme pocket residues-Arg38, Thr40, Gly41, and Phe46. In a previous simulation study by Sagnella and Straub, heme "cooling" in myoglobin was found to proceed via a spatially anisotropic "funneling" mechanism as a single-exponential process with a time constant of 5.9 ps. Topological variations in heme/protein connectivity and variations in the accessibility of the heme to the solvent are used to explain the distinctly different pathways and time scales for heme "cooling" in the two proteins.