Control of O-2 versus CO binding in myoglobin (Mb) is tuned by a distal histidine residue through steric and H-bonding interactions. These interactions have been evaluated via Car-Parrinello DFT calculations, whose efficiency allows full quantum mechanical treatment of the 13 closest residues surrounding the heme. The small (8degrees) deviation of the Fe-C-O bond angle from linearity results from the steric influence of a distal valine residue and not the distal histidine. H-bond energies were evaluated by replacing the distal histidine with the non-H-bonding residue isoleucine. Binding energies for CO and O-2 decreased by 0.8 and 4.1 kcal/mol for MbCO and MbO(2), in good agreement with experimental H-bond estimates. Ligand discrimination is dominated by distal histidine H-bonding, which is also found to stabilize a metastable side-on isomer of MbO(2) that may play a key role in MbO(2) photodynamics.