A system for determining a sample map for alignment measurements includes a metrology tool and a controller. The controller defines a full sampling map including a plurality of measurement locations. The controller directs the metrology tool to measure alignment at each measurement location of the full sampling map for a plurality of samples to generate a reference alignment dataset, generates candidate sampling maps, each being a subset of the full sampling map. The controller may further estimate alignment as a function of location based on the two or more candidate sampling maps at each measurement location of the full sampling map, and determine a working sampling map by comparing the estimated alignment to the reference alignment dataset and selecting the candidate sampling map having a smallest number of alignment estimates exceeding a selected tolerance.