Abstract: In recent years, the problem of progressive collapse of building structures has aroused widespread concern at home and abroad. As one of the most commonly used structure systems in engineering practice, the reinforced concrete (RC) frame structures have been widely involved in many existing progressive collapse studies. However, most of the studies were mainly based on deterministic and static analyses of column removal scenarios. In this study, the finite element (FE) model of a typical RC frame beam-column substructure is built based on OpenSees. Both static and dynamic progressive collapse analyses of the beam-column substructure are performed and validated against the experimental results. Furthermore, several structural models were generated for the uncertainty analyses by the Latin hypercube sampling method. The influences of various uncertainty factors are discussed, including the sectional geometries, material properties and so on. The results indicate that the catenary action plays a crucial role in RC frame beam-column substructures against progressive collapse. However, the use of 0.2 rad chord rotation as the failure index in the dynamic progressive collapse analyses is to a certain extent conservative. Moreover, according to the sensitivity analyses, the yield strength and ultimate strength of the longitudinal reinforcement are the major factors that affect the progressive collapse resistance of RC frame beam-column substructures.