A solution NMR spectroscopic study of the cyanide-inhibited, substrate-bound complex of uniformly N-15-labeled human heme oxygenase, hHO, has led to characterization of the active site with respect to the nature and identity of strong hydrogen bonds and the occupation of ordered water molecules within both the hydrogen bonding network and an aromatic cluster on the distal side. {H-1-N-15}-HSQC spectra confirm the functionalities of several key donors in particularly robust H-bonds, and {H-1-N-15}HSQC-NOESY spectra lead to the identification of three additional robust H-bonds, as well as the detection of two more relatively strong H-bonds whose identities could not be established. The 3D NMR experiments provided only a modest, but important, extension of assignments because of the loss of key TOCSY cross-peaks due to the line broadening from a dynamic heterogeneity in the active site. Steady-state NOES upon saturating the water signal locate nine ordered water molecules in the immediate vicinity of the H-bond donors, six of which are readily identified in the crystal structure. The additional three are positioned in available spaces to account for the observed NOES. N-15-filtered steady-state NOES upon saturating the water resonances and N-15-filtered NOESY spectra demonstrate significant negative NOES between water molecules and the protons of five aromatic rings. Many of the NOES can be rationalized by water molecules located in the crystal structure, but strong water NOES, particularly to the rings of Phe47 and Trp96, demand the presence of at least an additional two immobilized water molecules near these rings. The H-bond network appears to function to order water molecules to provide stabilization for the hydroperoxy intermediate and to serve as a conduit to the active site for the nine protons required per HO turnover.