In most reinforced concrete (RC) multistory buildings, shear walls are provided to resist lateral loads arising from wind and earthquakes of moderate to high magnitude. The quantity and location of these walls play a significant role in controlling the building response, reliability, and overall construction cost, and therefore need to be optimized. In the literature, shear wall quantity and location are optimized without due consideration of the desired reliability level, which leads to structural designs with unknown safety levels. This paper addresses this issue by introducing the desired reliability level as an additional constraint. The methodology is demonstrated with the help of a set of representative unsymmetrical and symmetrical RC shear wall-frame buildings subjected to the El-Centro earthquake. The results of the study illustrate that the reliability constraint is, in general, a governing constraint in the optimization process of RC shear wall-frame buildings subjected to earthquake forces. The study is expected to be useful for practicing engineers and researchers to achieve the desired level of safety in structural design.