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The effects of combinations of different types of irregularities have not been studied in details in the past and current seismic design codes do not address this issue appropriately. In this research, 76 regular and irregular bridges with irregularities in both superstructure and substructure were designed and evaluated to investigate the impact of combinations of irregularities on the seismic ductility demands. The irregularity parameters considered in this study include irregularities in span arrangement, different lengths of columns, different abutments support conditions and different stiffness of superstructure. The bridges were designed and checked according to AASHTO provisions. Inelastic time history analysis was conducted using OpenSees software and ductility demands in bridge columns for different bridge configurations were predicted. Predictions of ductility demands were based on the mean responses obtained using a number of ground motion records. Finally, the effect of considering displacement directions in predicting the mean bridge response (i.e., using different methods for predicting the mean response) for irregular and regular bridges was investigated. The results indicate that the combinations of irregularities can significantly increase the ductility demands in some cases compared to the case of regular bridges.