This paper presents a defocus-invariant image registration method for measuring the shifting value between two differently located patterns in an imaging sensor. Existing registration methods fail with unfocused images since features or regions of interest are degraded by defocus. In order to solve this problem, the proposed method consists of three stages: i) pre-generation of the set of point spread functions (PSFs) estimated in different focusing positions, ii) the geometric transformation estimation using estimated PSF data, and iii) registration using estimated transformation matrix. The proposed method improves out-of-focus degradation through estimation of PSF. For this reason, the proposed method can accurately estimate the difference of phase between two out-of-focus images. Furthermore, it can be applied to phase-difference detection auto focusing, and provide accurate auto focusing performance.