BACKGROUND: High-cost healthcare users (HCUs) are patients who use disproportionate healthcare resources compared to their peers. A better understanding of their co-morbidity status, medication use, and healthcare utilization is needed to improve health interventions and policies. OBJECTIVES: We aimed to: (1) synthesize what is known about HCUs and interventions for managing them, (2) characterize how HCUs differ from non-HCUs, and (3) explore the impact of medications and whether prescribing quality contributes to differences in healthcare costs and HCU status development. METHODS: We synthesized what is known about HCUs and used the GRADE framework to evaluate the evidence for interventions designed to improve their health. We conducted retrospective population-based matched cohort and case-control studies of incident older adult HCUs using health administrative data. We examined prescribing and medication costs over the non-HCU to HCU transition period and compared them to non-HCUs. We conducted logistic regression to evaluate associations between HCU status development and the use of high-cost drugs and potentially inappropriate medications. RESULTS: HCU interventions to date have shown inconsistent effects on clinical outcomes and healthcare costs and the overall quality of evidence supporting their efficacy is low. Compared to non-HCUs, HCUs have higher rates of polypharmacy, hospitalization, and mortality. Medications are the highest healthcare cost category in the pre-HCU year and these costs rise nearly 1.7-fold in the HCU year. High-cost drug use increases significantly during the HCU transition period and 3.6% achieve HCU status based on drug costs alone. Use of several potentially inappropriate medications and high-cost drugs significantly increase the odds of HCU development. CONCLUSIONS: Medications can contribute to high-cost healthcare directly through drug costs alone or indirectly through adverse effects on health. Medication optimization interventions and policies to reduce inappropriate medication use and ensure cost-effective medication use are needed to manage high-cost healthcare and prevent HCU development. / Thesis / Doctor of Philosophy (PhD) / High-cost healthcare users (HCUs) are patients who use disproportionate healthcare resources compared to their peers. More research is needed to better understand HCUs to design interventions to improve their health outcomes and costs. In this thesis, we evaluated what previous studies have discovered about HCUs and we used Ontario’s health system data to explore whether the quality of prescribing and medication use in older adults influences their risk of becoming a HCU. We found that current interventions for HCUs have had inconsistent effects on improving health outcomes and costs. We also found two medication-related factors contributing to the risk of becoming an older adult HCU: (1) use of very expensive medications, and (2) use of potentially inappropriate medications where the risk of harm may outweigh potential benefits. Interventions and health policies to optimize the appropriate and cost-effective use of medications are needed to manage high-cost healthcare and prevent HCU development.