The present invention relates generally to selecting optimum patterns based on diffraction signature analysis, and more particularly to, using the optimum patterns for mask-optimization for lithographic imaging. A respective diffraction map is generated for each of a plurality of target patterns from an initial larger set of target patterns from the design layout. Diffraction signatures are identified from the various diffraction maps. The plurality of target patterns is grouped into various diffraction-signature groups, the target patterns in a specific diffraction-signature group having similar diffraction signature. A subset of target patterns is selected to cover all possible diffraction-signature groups, such that the subset of target patterns represents at least a part of the design layout for the lithographic process. The grouping of the plurality of target patterns may be governed by predefined rules based on similarity of diffraction signature. The predefined rules comprise coverage relationships existing between the various diffraction-signature groups.