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This paper discusses and compares two recently developed methodologies for the prediction of damage accumulation in structures subjected to multiple earthquakes within their lifetime, one based on a regression model and one based on a Markov-chain based approach. A stochastic earthquake hazard model is considered for generating sample sequences of ground motion records that are then used to estimate the probabilistic distribution of the damage accumulated during the time interval of interest using the various methodologies. A simulation-based approach provides a reference solution against which the other methodologies are compared. Besides assessing the effectiveness and accuracy of the two methodologies, some improvements of the regression model are proposed and evaluated. The comparison between the methodologies is carried out by examining a reinforced concrete (RC) bridge pier model and using the Park–Ang damage index to describe the damage accumulation. The study results demonstrate the importance of considering the possibility of occurrence of multiple shocks in estimating the life-cycle performance of structures and highlight strengths and drawbacks of the investigated methodologies.