Presented herein is a seismic design approach developed for a proposed infill wall “structural fuse” system for use in building frames. The purpose of this system is to prevent damage to frame or infill walls due to infill wall-frame in-teraction during potentially damaging earthquakes by isolating them through a “sacrificial” component or a structural fuse. The design approach includes a procedure for design and application of the fuse system in a multi-bay, multi-story build-ing with moment resisting frames. The empirical equation developed to predict the in-plane strength of masonry infill walls equipped with structural fuse is discussed. A calculation method is suggested to specify an appropriate fuse element capacity arrangement in a building frame in order to achieve desirable and controlled structural performance. The design procedure is shown through application to two buildings used for example, a low-rise (4-story) and a mid-rise (8-story) building. The result of the study demonstrates that the proposed isolation system has merits and can potentially improve the seismic performance of masonry infill walls by protecting the infill wall and the frame from damages due to their in-teraction.