Thick, segmented crystalline scintillators have shown increasing promise as replacement x-ray converters for the phosphor screens currently used in active matrix flat-panel imagers (AMFPIs) in radiotherapy, by virtue of providing over an order of magnitude improvement in the detective quantum efficiency (DQE). However, element-to-element misalignment in current segmented scintillator prototypes creates a challenge for optimal registration with underlying AMFPI arrays, resulting in degradation of spatial resolution. To overcome this challenge, a methodology involving the use of a relatively high resolution AMFPI array in combination with novel binning techniques is presented. The array, which has a pixel pitch of 0.127 mm, was coupled to prototype segmented scintillators based on BGO, LYSO and CsI:Tl materials, each having a nominal element-to-element pitch of 1.016 mm and thickness of ∼1 cm. The AMFPI systems incorporating these prototypes were characterized at a radiotherapy energy of 6 MV in terms of modulation transfer function, noise power spectrum, DQE, and reconstructed images of a resolution phantom acquired using a cone-beam CT geometry. For each prototype, the application of 8 × 8 pixel binning to achieve a sampling pitch of 1.016 mm was optimized through use of an alignment metric which minimized misregistration and thereby improved spatial resolution. In addition, the application of alternative binning techniques that exclude the collection of signal near septal walls resulted in further significant improvement in spatial resolution for the BGO and LYSO prototypes, though not for the CsI:Tl prototype due to the large amount of optical cross-talk resulting from significant light spread between scintillator elements in that device. The efficacy of these techniques for improving spatial resolution appears to be enhanced for scintillator materials that exhibit mechanical hardness, high density and high refractive index, such as BGO. Moreover, materials that exhibit these properties as well as offer significantly higher light output than BGO, such as CdWO4, should provide the additional benefit of preserving DQE performance.