In current slope reliability analysis, the failure probability might be wrongly calculated because of the inadequate consideration of anisotropic spatial variability of soil parameters. Therefore, a random finite difference method (RFDM) framework considering anisotropic spatial variability is established. Taking the general anisotropic spatial variability slope as a reference slope, the influence of anisotropic spatial variability on slope reliability is systematically studied from the aspects of fluctuation range direction structure, cross-correlation coefficient, variation coefficient and fluctuation range. The results show that the coordinate-transformation-based anisotropic random field simulation method can effectively characterize anisotropic spatial variability of soil parameters. Strain-clustering-based slope critical slip surface searching algorithm can accurately determine the complex critical sliding surface of slope. Compared with the general anisotropic spatial variability, the slope failure probability is overestimated and greatly underestimated when considering rotational anisotropy and transverse anisotropy, respectively. In addition, considering isotropic random fields can overestimate and underestimate the slope failure probability in case of greater and smaller scale of fluctuation, respectively.