The rebinding of CO to myoglobin (Mb) from locations around the active site is studied using a combination of molecular dynamics and stochastic simulations for native and L29F mutant Mb. The interaction between the dissociated ligand and the protein environment is described by the recently developed fluctuating three-point charge model for the CO molecule. Umbrella sampling along trajectories, previously found to sample the binding site (13) and the Xe4 pocket, is used to construct free-energy profiles for the ligand escape. On the basis of the Smoluchowski equation, the relaxation of different initial population distributions is followed in space and time. For native Mb at room temperature, the calculated rebinding times are in good agreement with experimental values and give an inner barrier of 4.3 kcal/mol between the docking site B (Mb(...)CO) and the A state (bound MbCO), compared to an effective barrier, H-eff, of 4.5 kcal/mol and barriers into the majority conformation A(1) and the minority conformation A(3) of 2.4 and 4.3 kcal/mol, respectively. In the case of the L29F mutant, the free-energy surface is flatter and the dynamics is much more rapid. As was found in experiment, escape to the Xe4 pocket is facile for L29F whereas, for native Mb, the barriers to this site are larger. At lower temperatures, the rebinding dynamics is delayed by orders of magnitude also due to increased barriers between the docking sites.