A new model for catalysis of human carbonic anhydrase II is suggested. The model is based on the X-ray structure of the hydrogen bond network in the catalytic site. The outer part of the network is proposed to adjust the pKa of the catalytic site to the experimentally observed value of about 7. The inner part of the network is proposed to become a low-barrier hydrogen bond network in the transition state. The energy released in forming the low-barrier hydrogen bond network is used to catalyse the interconversion of CO2 and HCO3: The suggested molecular mechanism is consistent with the generally accepted kinetic scheme for human carbonic anhydrase II. © 2002 Elsevier Science Ltd. All rights reserved.