The main objective of this paper is to study the structural performance of a high-rise structure when alternative lightweight material known as cross-laminated timber was used as a slab in floor system in lieu of conventional reinforced concrete slab. A numerical case study was conducted using a highly irregular RC frame building with its two 60-story towers joined at the top. Three major analyses were considered. First, modeling and analyzing the building with an RC slab was conducted to determine the design reference. Second, substituting the RC slab with the CLT slab was performed using the same building skeleton. Third, redesigning and optimizing the building skeleton with that CLT to observe skeleton material saving obtained using the same structural performance criteria. Major lateral loads applicable in the Eastern Province of Saudi Arabia were inputted. Strengths and serviceability requirements for floor diaphragm and lateral load resisting system were checked first before performing a comparative analysis between traditional RC and CLT slabs as floor diaphragm. The structural performance criteria to be used for comparative study between RC and CLT slabs included total drift, inter-story drift due to lateral loads, and base reactions. Structural periods and acceleration responses for each floor were investigated and contrasted with the existing building code. The foundation demand was also investigated based on the structural weight and reactions generated from the RC and CLT floor systems.