This research investigates the influence of different masonry panel configurations on the seismic performance of reinforced concrete (RC) frame buildings, with particular attention to the effects of openings and variations in the spatial distribution of infills across multiple stories. The primary objective is to understand how these configurations modify structural stiffness, energy dissipation capacity, and damage patterns during earthquake loading. To achieve this, a comprehensive parametric study was performed, evaluating a range of infill arrangements and discontinuities that may occur in real construction scenarios. Numerical models of the RC frames were developed, where masonry infills were represented using equivalent single-strut models capable of capturing their contribution to lateral strength. Nonlinear time–history analyses were then carried out using incrementally intensified earthquake ground motions, in accordance with the incremental dynamic analysis (IDA) methodology. From these simulations, fragility functions were derived through intensity measure (IM)-based procedures, enabling systematic comparison among different structural cases. These fragility curves provide critical insight into the likelihood of exceeding various performance or damage states. The results demonstrate that both the distribution pattern of masonry infills and the presence of openings have a substantial impact on seismic response, with certain configurations exhibiting markedly higher vulnerability and reduced resilience under strong ground shaking.