The performance of the effective fragment potential (EFP) method, a quantum mechanical-molecular mechanical (QM-MM) method, to reproduce fully quantum mechanical results has been investigated. The enthalpies of hydration for 10 oxyanions (ClO4-, HSO4-, NO3-, H2PO4-, HCO3-, HCO2-, SO42-, HPO42-, CO32-, and PO43-) by one to four water molecules were studied. For monohydrate systems exhibiting small to moderate amounts of charge transfer (ClO4-, HSO4-, NO3-, H2PO4- HCO3-, and HCO2-), the EFP method reproduces Hartree-Fock (HF) differential enthalpies of hydration remarkably well (mean difference = -0.1 and standard deviation = 0.9 kcal/mol). The EFP and HF calculations also successfully reproduce the available experimental data (EFP: mean difference = 2.0 and standard deviation = 0.8 kcal/mol; HF: mean difference = 1.8 and standard deviation = 1.0 kcal/mol). MP2 calculations show only a slight improvement in agreement with experiment over the HF calculations, indicating a small electron correlation effect. For the high charge transfer monohydrate systems (SO42-, HPO42-, CO32-, and PO43-), the EFP method is less successful in reproducing HF differential enthalpies of hydration. The agreement between EFP and HF results improves, however, with the number of water molecules. These results suggest reduced variational space (RVS) analysis can be used to predict which systems may pose (charge transfer) problems for the EFP method.