A significant portion of residential areas of Turkey is located in active earthquake zones. In Turkey occurred major earthquakes in last twenty years, such as Erzincan (1992), Kocaeli and Duzce (1999), Bingol (2003), Van (2011). These earthquakes have demonstrated that reinforced concrete (RC) buildings having horizontal and vertical irregularities are significantly damaged, which in turn most of them are collapsed. Architectural design and arrangement of load-bearing system have important effect on RC building since architectural design criteria in design process provide opportunity to make this type of buildings safer and economical under earthquake loads. This study aims to investigate comparatively the effects of weak story irregularity on earthquake behavior and rough construction costs of RC buildings by considering different soil-conditions given in the Turkish Earthquake Code. With this aim, Sta4-CAD program based on matrix displacement method is utilized. Considering that different story height and compressive strength of concrete, and infill walls or their locations are the variables, a set of structural models are developed to determine the effect of them on earthquake behavior and rough construction costs of RC buildings. In conclusion, some recommendations and results related to making RC buildings safer and more economical are presented by comparing results obtained from structural analyses.