Removal of load-bearing elements such as columns, can rapidly lead to structural failures and the compromise of building stability. These failures can be initiated by minor damage but can ultimately culminate in catastrophic events. In the line of progressive collapse resistance of conventional urban buildings, extensive studies have so far been performed; though relatively little attention has been paid to the impact of earthquakes on structural resilience under such failures, this is particularly the case in irregular structures as these structures have hardly received much attention. In this research, considering the presence of setback irregularities in many structures, the impact of the column removal scenario after different earthquake intensities of low, medium, and high on over 60 steel moment frame structures with 5 and 10 stories is investigated. The structures are first categorized into four vulnerability groups, from maximum to minimum resistance against progressive collapse, based on the damage percentage. After applying 12 earthquake records at the MCE level, the cases studied are assessed under column removal scenarios at different spans and stories. The results reveal that earthquakes, elevate the risk of progressive collapse. Moreover, increasing setback irregularity up to 13.33 % improves structural performance against progressive collapse, reducing responses by 21 % on average compared to regular structures. However, at higher setback irregularity percentages, responses increase by 82 % on average, diminishing structural resistance. Setting upper limits for this type of irregularity and imposing constraints on design parameters, while modifying minimum base shear and maximum period limit, can significantly reduce progressive collapse potential.