The partial Hessian vibrational analysis (PHVA), in which only a subblock of the Hesssian matrix is diagonalized to yield vibrational frequencies for partially optimized systems, is extended to the calculation of vibrational enthalpy and entropy changes for chemical reactions. The utility of this method is demonstrated for various deprotonation reactions by reproducing full HVA values to within 0.1–0.4 kcal/mol, depending on the number atoms included in the PHVA. When combined with the hybrid effective fragment potential method [Gordon MS, et al. (2001) J Phys Chem A 105:293–307], the PHVA method can provide (harmonic) free-energy changes for localized chemical reactions in very large systems.