Changing the distal histidine (H64) of sperm-whale myoglobin into any of the following residues-valine, leucine, methionine, glycine, or phenylalanine-causes a dramatic improvement in the reversibility (electron-transfer kinetics) and reproducibility of the direct electrochemistry. Cyclic voltammograms of native or wild-type recombinant myoglobin are irreversible (in the electrochemical sense) and critically dependent on the condition of the sample and electrode. By contrast, the H64 mutants display quasi-reversible electrochemistry much more typical of results obtained with true electron-transfer proteins. The difference in activity correlates sharply with alterations to the distal-pocket H-bonding network, which in the native protein comprises the H2O that is coordinated to Fe(III), the N-epsilon of H64, and the "lattice" extending from arginine-45 to the heme periphery. It is proposed that this H-bond network increases the electron-transfer activation energy by coupling the displacement of Fe(lII)-coordinated H2O to higher reorganization requirements, including that of solvent H2O molecules near the heme periphery. The poor reproducibility and extreme sensitivity of the electrochemical response to experimental conditions is rationalized by the microscopic model for protein electrochemistry which predicts that the waveshape and potential positions for inherently irreversible (sluggish) systems will be critically dependent on the state of the electrode surface.