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Real-time spatial referencing is an important alternative to tracking for designing spatially aware ophthalmic instrumentation for procedures such as laser photocoagulation and perimetry. It requires independent, fast registration of each image frame from a digital video stream (1024 × 1024 pixels) to a spatial map of the retina. Recently, we have introduced a spatial referencing algorithm that works in three primary steps: 1) tracing the retinal vasculature to extract image feature (landmarks); 2) invariant indexing to generate hypothesized landmark correspondences and initial transformations; and 3) alignment and verification steps to robustly estimate a 12-parameter quadratic spatial transformation between the image frame and the map. The goal of this paper is to introduce techniques to minimize the amount of computation for successful spatial referencing. The fundamental driving idea is to make feature extraction subservient to registration and, therefore, only produce the information needed for verified, accurate transformations. To this end, the image is analyzed along one-dimensional, vertical and horizontal grid lines to produce a regular sampling of the vasculature, needed for step 3) and to initiate step 1). Tracing of the vascular is then prioritized hierarchically to quickly extract landmarks and groups (constellations) of landmarks for indexing. Finally, the tracing and spatial referencing computations are integrated so that landmark constellations found by tracing are tested immediately. The resulting implementation is an order-of-magnitude faster with the same success rate. The average total computation time is 31.2 ms per image on a 2.2-GHz Pentium Xeon processor.