Currently available performance-based methodologies for assessing the fragility of structures subjected to tsunami neglect the effects of tsunami-induced vertical loads due to internal buoyancy. This paper adopts a generalized methodology for the performance assessment of structures that integrates the effects of buoyancy loads on interior slabs during a tsunami inundation. The methodology is applied in the fragility assessment of three case-study frames (low, mid and high-rise), representative of existing masonry-infilled reinforced concrete (RC) buildings typical of Mediterranean region. The paper shows the effect of modelling buoyancy loads on damage evolution and fragility curves associated with different structural damage mechanisms for existing RC frames with breakaway infill walls including consideration of blow-out slabs. The outcomes attest that buoyancy loads affect the damage assessment of buildings during a tsunami, especially in the case of mid and high-rise structures with blow-out slabs. The rate of occurrence of slabs uplift failure increases with the number of stories of the building, indicating the need to account for such damage mechanism when assessing the performance of structures. It is also found that buoyancy loads slightly affect the fragility curves associated to other structural damage mechanisms for existing RC buildings commonly monitored for fragility assessment.