We recently described a method to compute accurate quantum mechanical free energies Rod, T. H.; Ryde, U. Phys. Rev. Lett. 2005, 94, `138302. The method, which we term quantum mechanical thermodynamic cycle perturbation (QTCP), employs a molecular mechanics force field to sample phase space and, subsequently, a thermodynamic cycle to estimate QM/MM free energy changes. Here, we discuss the methodology in detail and test an approach based on a different thermodynamic cycle. We also show that a new way of treating hydrogen link atoms makes the free energy changes converge faster and that extrapolation to higher accuracy can be performed. We finally discuss the quantum mechanical free energy (QM/MMFE) method in the framework of the QTCP method. All methods considered are applied to the methylation of catecholate catalyzed by catechol O-methyltransferase. We compute the free energy barrier for the reaction by computing free energy changes in steps between fixed OM regions along a predetermined reaction pathway. Using the QTCP approach, an extrapolated activation free energy of 69 kJ/mol for the forward reaction and 90 kJ/mol for the reverse reaction are obtained at the level of the B3LYP functional and the 6-311++G(2d,2p) basis set. The value for the forward reaction is in excellent agreement with the experimental value of 75 kJ/mol. Results based on the QM/MM-FE method differ by less than 10 kJ/mol from those values, indicating that QM/MM-FE may be a fairly accurate and cheap alternative to calculate QM/MM free energy changes. Moreover, the results are compared to barriers obtained with a fixed molecular mechanics environment as well as with structures optimized in a vacuum. All the computed free energy barriers are well converged. A major approximation in the current implementation of the QTCP method is that the QM region is fixed. The approximation leads to well-converged free energy barriers, which has been a problem in similar studies.