We have explored possible mechanisms for the formation of the catalytically active Ni_a–S state of the enzyme, nickel iron hydrogenase, from the Ni^*_r (ready) or Ni^*_u (unready) state, by reaction with H₂, using density functional theory calculations with the BP86 functional in conjunction with a DZVP basis set. We find that for the reaction of the ready state, which is taken to have an –OH bridge, the rate determining step is the cleavage of H₂ at the Ni³⁺ centre with a barrier of ∼15 kcal mol⁻¹. We take the unready state to have a –OOH bridge, and find that reaction with H₂ to form the Ni_r–S state can proceed by two possible routes. One such path has a number of steps involving electron transfer, which is consistent with experiment, as is the calculated barrier of ∼19 kcal mol⁻¹. The alternative pathway, with a lower barrier, may not be rate determining. Overall, our predictions give barriers in line with experiment, and allow details of the mechanism to be explored which are inaccessible from experiment.