Abstract: The present invention relates to a method, system and software for registration of a subject data set with a reference data set. The method of the invention includes the steps of: specifying three or more landmarks (1, 2, 3) in a first data set (8); specifying three or more corresponding landmarks (4, 5, 6) in a second data set (7); registering the first data set to the second data set using the landmarks; for at least one of the landmarks (1), determining a first patch (40) around the landmark (1) and a second patch (43) around the corresponding landmark (4); and refining the registration between the first and second data set using the patches (40, 43). A system and software for registration of a subject data set (7) with a reference data set (8) are also disclosed.