It is well known that alpha-chymotrypsin can exist in two major conformational states, only one of which is active. We have examined the pH (pH 2.0--11.0) and salt (ionic strength 0.01--1.0) dependence of the transition between the active and inactive forms in detail. At low pH (pH 2.0--6.0) the equilibrium is very dependent on salt concentration, with high salt concentrations effectively stabilizing the active conformation. This apparent stabilization is an artifact due to the salt-dependent dimerization of alpha-chymotrypsin, and our data show that only active species form dimers and higher aggregates. At neutral pH (6.0--8.0) dimerization is absent, yet an ionic strength dependence remains. The effects show no lyotropic order and appear to be due to preferential salt binding to the active conformation at one or possibly a few sites. Above pH 6 (pH 6.0--11.0), the pH dependence can be described by a two-ionization mechanism at all ionic strengths. We report values for all seven equilibrium constants in the proposed mechanism at four ionic strengths (mu = 0.01, 0.05, 0.2, and 1.0). The transition is the first "refolding" transition to be studied at high precision, but, even so, certain decisions about the mechanism must await higher experimental precision not available with present methods.