Recently, the hydrolysis of nerve agents by Lewis acid catalysts has attracted considerable attention. The development of molecular catalysts, such as polyoxometalates (POMs) with Lewis acidic sites, is helpful to improve degradation efficiency and understand the catalytic mechanism at a molecular level. Herein, two novel Keggin-type POMs, namely, mono-Sc-substituted K-4[Sc(H2O)PW11O39]center dot 22H(2)O center dot 2(CH3COOK) (1) and di-Sc-substituted Na-7[Sc-2(CH3COO)(2)PW10O38]center dot 10H(2)O center dot 2CH(3)COONa (2), have been successfully synthesized and thoroughly characterized by routine techniques. To our knowledge, 1 and 2 represent the first example of discrete Sc-substituted Keggin clusters. Compared with the reported Sc-containing POMs, 1 and 2 exhibit relatively good solubility and stability in aqueous solution, as evidenced by 31 P nuclear magnetic resonance spectroscopy and Fourier-transform infrared spectroscopy. The two Sc-substituted POMs can effectively catalyze the hydrolytic decontamination of dimethyl 4-nitrophenyl phosphate (DMNP), a nerve agent simulant, at near- neutral pH. Notably, the catalytic performance of 2 (conversion: 97%) is much better than that of 1 (conversion: 28%). It is found that the different coordination environment of Sc is the key factor to impact their activity. Mechanistic studies including the control experiments and spectroscopy analysis (C-13 nuclear magnetic resonance spectroscopy and electrospray ionization mass spectrometry) show that under the turnover conditions the coordinated acetate dissociates from 2 and the exposed coordinatively unsaturated Sc center is more active than the water-coordinated Sc in 1 for binding with DMNP.