The static second-order nonlinear optical (NLO) responses of a series of lacunary γ-Keggin polyanion derivatives, [XM 2 W 10 O 38 (μ-OH) 2 ] n − (X=Si IV , Ge IV , P V , As V , M=Al III , Ti IV , V V ; X=Zn II , V V , M=Al III ), were investigated by using density functional theory (DFT) methods. The results show that the molecular NLO activity of lacunary Keggin POM derivatives can be modified by replacing the central heteroatom (X) and the substituted addenda metal atom (M), which reveals the general rules to design the system with large optical nonlinearity.