The relative permeability functions of two-phase reservoirs are extensively used in modern reservoir-engineering theories for calculations and numerical simulations. In recent years, the theory of anisotropic reservoir development has advanced rapidly, and the anisotropic absolute permeability of reservoirs has been characterized and applied accurately. However, if only the anisotropy of absolute permeability is considered while neglecting the anisotropy of relative permeability, the effective permeability used in the calculations will differ significantly from that of an actual reservoir. In this study, an anisotropy experiment on two-phase relative permeability, with oil and water, was conducted using natural sandstone without fractures, which demonstrated the existence of anisotropy in relative permeability and analyzed its mechanism. The properties and calculation methods for anisotropic relative permeability were studied under the symmetry groups of a rhombic system. Numerical simulations of the reservoir considering anisotropic relative permeability were performed. The results demonstrated that the anisotropic relative permeability significantly affected the development of the oil reservoir, which is primarily indicated by the significant difference in the seepage direction of oil and water, and the complicated oil/water distribution. The results of this study differed significantly from the conventional understanding of remaining oil distribution. The deformed well pattern established for the anisotropy of the absolute permeability indicated a decrease in the oil-recoveryratio.