Carbonic anhydrases catalyze the interconversion of CO(2) to HCO(3)(-), with a subsequent proton-transfer (PT) step. PT proceeds via a proposed hydrogen-bonded water network in the active-site cavity that is stabilized by several hydrophilic residues. A joint X-ray and neutron crystallographic study has been initiated to determine the specific water network and the protonation states of the hydrophilic residues that coordinate it in human carbonic anhydrase II. Time-of-flight neutron crystallographic data have been collected from a large ( approximately 1.2 mm(3)) hydrogen/deuterium-exchanged crystal to 2.4 A resolution and X-ray crystallographic data have been collected from a similar but smaller crystal to 1.5 A resolution. Obtaining good-quality neutron data will contribute to the understanding of the catalytic mechanisms that utilize water networks for PT in protein environments.