Detection of vascular bifurcations is a challenging task in multimodal retinal image registration. Existing algorithms based on bifurcations usually fail in correctly aligning poor quality retinal image pairs. To solve this problem, we propose a novel highly distinctive local feature descriptor named partial intensity invariant feature descriptor (PIIFD) and describe a robust automatic retinal image registration framework named Harris-PIIFD. PIIFD is invariant to image rotation, partially invariant to image intensity, affine transformation, and viewpoint/perspective change. Our Harris-PIIFD framework consists of four steps. First, corner points are used as control point candidates instead of bifurcations since corner points are sufficient and uniformly distributed across the image domain. Second, PIIFDs are extracted for all corner points, and a bilateral matching technique is applied to identify corresponding PIIFDs matches between image pairs. Third, incorrect matches are removed and inaccurate matches are refined. Finally, an adaptive transformation is used to register the image pairs. PIIFD is so distinctive that it can be correctly identified even in nonvascular areas. When tested on 168 pairs of multimodal retinal images, the Harris-PIIFD far outperforms existing algorithms in terms of robustness, accuracy, and computational efficiency. © 2006 IEEE.