Agent-based epidemic simulation (ABES) is a powerful and realistic approach for studying the impacts of disease dynamics and complex interventions on the spread of an infection in the population. Among many ABES systems, EpiSimdemics comes closest to the popular agent-based epidemic simulation systems developed by Eubank, Longini, Ferguson, and Parker. EpiSimdemics is a general framework that can model many reaction-diffusion processes besides the Susceptible-Exposed-Infectious-Recovered (SEIR) models. This model allows the study of complex systems as they interact, thus enabling researchers to model and observe the socio-technical trends and forces. Pandemic planning at the world level requires simulation of over 6 billion agents, where each agent has a unique set of demographics, daily activities, and behaviors. Moreover, the stochastic nature of epidemic models, the uncertainty in the initial conditions, and the variability of reactions require the computation of several replicates of a simulation for a meaningful study. Given the hard timelines to respond, running many replicates (15-25) of several configurations (10-100) (of these compute-heavy simulations) can only be possible on high-performance clusters (HPC). These agent-based epidemic simulations are irregular and show poor execution performance on high-performance clusters due to the evolutionary nature of their workload, large irregular communication and load imbalance. For increased utilization of HPC clusters, the simulation needs to be scalable. Many challenges arise when improving the performance of agent-based epidemic simulations on high-performance clusters. Firstly, large-scale graph-structured computation is central to the processing of these simulations, where the star-motif quality nodes (natural graphs) create large computational imbalances and communication hotspots. Secondly, the computation is performed by classes of tasks that are separated by global synchronization. The non-overlapping computations cause idle times, which introduce the load balancing and cost estimation challenges. Thirdly, the computation is overlapped with communication, which is difficult to measure using simple methods, thus making the cost estimation very challenging. Finally, the simulations are iterative and the workload (computation and communication) may change through iterations, as a result introducing load imbalances. This dissertation focuses on developing a cost estimation model and load balancing schemes to increase the runtime efficiency of agent-based epidemic simulations on high-performance clusters. While developing the cost model and load balancing schemes, we perform the static and dynamic load analysis of such simulations. We also statically quantified the computational and communication workloads in EpiSimdemics. We designed, developed and evaluated a cost model for estimating the execution cost of large-scale parallel agent-based epidemic simulations (and more generally for all constrained producer-consumer parallel algorithms). This cost model uses computational imbalances and communication latencies, and enables the cost estimation of those applications where the computation is performed by classes of tasks, separated by synchronization. It enables the performance analysis of parallel applications by computing its execution times on a number of partitions. Our evaluations show that the model is helpful in performance prediction, resource allocation and evaluation of load balancing schemes. As part of load balancing algorithms, we adopted the Metis library for partitioning bipartite graphs. We have also developed lower-overhead custom schemes called Colocation and MetColoc. We performed an evaluation of Metis, Colocation, and MetColoc. Our analysis showed that the MetColoc schemes gives a performance similar to Metis, but with half the partitioning overhead (runtime and memory). On the other hand, the Colocation scheme achieves a similar performance to Metis on a larger number of partitions, but at extremely lower partitioning overhead. Moreover, the memory requirements of Colocation scheme does not increase as we create more partitions. We have also performed the dynamic load analysis of agent-based epidemic simulations. For this, we studied the individual and joint effects of three disease parameter (transmissiblity, infection period and incubation period). We quantified the effects using an analytical equation with separate constants for SIS, SIR and SI disease models. The metric that we have developed in this work is useful for cost estimation of constrained producer-consumer algorithms, however, it has some limitations. The applicability of the metric is application, machine and data-specific. In the future, we plan to extend the metric to increase its applicability to a larger set of machine architectures, applications, and datasets. / Ph. D.