© 2018 Elsevier B.V. The K-edge Subtraction (KES) imaging method is a very powerful synchrotron method which allows functional imaging of biological subjects. KES gives a simultaneous image of the contrast element and an anatomical image from the same data set. For biological subjects, an imaging system that uses focused multiple (two or more) x-ray energy beams to form the images, reduces motion artifact that can be misleading. However, the crossing of beams gives rise to another artifact, termed the “crossover” artifact, if the subject is not at the focus or is spatially extended around the focus. This artifact is addressed in this paper for KES which uses multiple x-ray energy focused beams. The development of multiple energy imaging systems have shown a great deal of utility in extracting multiple contrast materials. Nevertheless, the need for reduction of the crossover artifact is essential for the effective use of these systems for imaging of biological subjects, which will help prevent unnecessary re-imaging, reduce unusable images and dose to the subjects. A unified approach to modeling and reducing of crossover artifact in multiple x-ray energy KES is presented.