Steel frames are usually designed with a column overdesign factor (COF) to ensure the preferable failure mode, which is yielding of all beams in flexure prior to the yielding of columns. In the present study, in consideration of the uncertainties of earthquake loads and the strengths of structural members, the failure modes of multistory ductile frame structures are investigated probabilistically. The first-order reliability method (FORM) and the dimension reduction integration (DRI) method with fourth-moment standardization are applied in the investigation. The Ai distribution of load along the height of the frame is taken into account. By comparing the Ai distribution and the triangular distribution results, it is observed that the target COF requirement is affected by the load distribution. To evaluate the target COF requirement that probabilistically avoids undesirable story collapse modes, the system reliability must be considered. In the present paper, the concept of system reliability is introduced in the determination of the target COF. It is observed that the target values of COF considering system reliability are higher than those of the most likely failure mode. This study was conducted for different reliability levels and the corresponding COF values are presented in this paper.