A method of registering 3-dimensional digitized images to 2-dimensional digitized images during a medical procedure includes providing a pair of correctly-registered training images L={lr, lf} and their joint intensity distribution pl(ir, if), wherein ir and if are reference and floating images, respectively, providing a pair of observed images O={or, of} and their joint intensity distribution po(ir, if), mapping a marginal intensity distribution of the observed pair O={or, of} to a marginal intensity distribution of the training pair L={lr, lf}, and estimating a set of parameters T that registers image of to image or by maximizing a weighted sum of a Jensen-Shannon divergence (JSD) of a joint intensity distribution of the observed pair and a joint intensity distribution of the training pair and a similarity measure between the observed images.