Image registration of biological data is challenging as complex deformation problems are common. Possible deformation effects can be caused in individual data preparation processes, involving morphological deformations, stain variations, stain artifacts, rotation, translation, and missing tissues. The combining deformation effects tend to make existing automatic registration methods perform poor. In our experiments on serial histopathological images, the six state of the art image registration techniques, including TrakEM2, SURF + affine transformation, UnwarpJ, bUnwarpJ, CLAHE + bUnwarpJ and BrainAligner, achieve no greater than 70% averaged accuracies, while the proposed method achieves 91.49% averaged accuracy. The proposed method has also been demonstrated to be significantly better in alignment of laser scanning microscope brain images and serial ssTEM images than the benchmark automatic approaches (p < 0.001). The contribution of this study is to introduce a fully automatic, robust and fast image registration method for 2D image registration.