In this paper, we investigate a new method to enforce topology preservation on two/three-dimensional deformation fields for non-parametric registration problems involving large-magnitude deformations. The method is composed of two steps. The first one consists in correcting the gradient vector field of the deformation at the discrete level, in order to fulfill a set of conditions ensuring topology preservation in the continuous domain after bilinear interpolation. This part, although related to prior works by Karacali and Davatzikos (Estimating Topology Preserving and Smooth Displacement Fields, B. Karacali and C. Davatzikos, IEEE Transactions on Medical Imaging, vol. 23(7), 2004), proposes a new approach based on interval analysis and provides, unlike their method, uniqueness of the correction parameter α at each node of the grid, which is more consistent with the continuous setting. The second one aims to reconstruct the deformation, given its full set of discrete gradient vector field. The problem is phrased as a functional minimization problem on a convex subset K of an Hilbert space V. Existence and uniqueness of the solution of the problem are established, and the use of Lagrange's multipliers allows to obtain the variational formulation of the problem on the Hilbert space V. The discretization of the problem by the finite element method does not require the use of numerical schemes to approximate the partial derivatives of the deformation components and leads to solve two/three uncoupled sparse linear subsystems. Experimental results in brain mapping and comparisons with existing methods demonstrate the efficiency and the competitiveness of the method. © 2012 SPIE.