BACKGROUND: Super-utilizers are individuals with disproportionately high inpatient and emergency department (ED) use, and mostly have multiple chronic conditions and use multiple concurrent medications. They place a substantial burden on the U.S. healthcare system and have become the focus of policy initiatives aimed at reducing their disproportionate inpatient and ED use. Medication management is critical for these patients since nonadherence to essential chronic medications is associated with poor health outcomes, and higher health care utilization and costs. OBJECTIVES: This dissertation employed a three empirical research papers approach to study the following aims: (1) the prevalence and patterns of medication nonadherence to essential chronic medications in Medicare super-utilizers with chronic conditions, and to identify the factors associated with medication nonadherence, with special emphasis on factors including mental illness and use of opioid medications, (2) examine associations between medication nonadherence, and inpatient and ED use, and to evaluate other risk factors associated with health care utilization in Medicare super-utilizers with chronic conditions, and (3) examine the impact of the SafeMed Program, a care transitions program with a focus on medication management, on medication use and adherence among publicly insured super-utilizers with chronic conditions. METHODS: This dissertation was based on patients eligible for the SafeMed Program, a care transitions program with a focus on medication management. The SafeMed Program targeted publicly insured super-utilizers with chronic conditions who were admitted to three hospitals that were part of a non-profit hospital system in Memphis, TN. The study sample included Medicare or TennCare insured adults who met the SafeMed Program eligibility criteria, had continuous medication coverage, and filled at least one of the drug classes used to treat hypertension, congestive heart failure, coronary artery disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), or asthma. Papers 1 and 2 were retrospective panel data analyses of the 2-year baseline data for Medicare Part D beneficiaries meeting the SafeMed Program eligibility criteria. Association between various factors and medication nonadherence was examined using random effects models with a binary distribution. Association between medication nonadherence and inpatient and ED utilization was examined using fixed effects negative binomial analyses. Paper 3 used a prospective quasi-experimental study design to examine the effectiveness of the SafeMed Program on medication use and adherence among SafeMed participants compared with patients in a control group using a difference in differences (DID) approach. RESULTS: Paper 1 demonstrated that the proportion of patients who were nonadherent to their essential chronic disease medications ranged from 45.7% to 58.4%, with the highest rate for COPD/Asthma medications (54.3% to 64.4%). In the multivariate analysis examining predictors of medication nonadherence, we found that compared with patients who did not use any opioid medication in the previous period, patients using >4 opioid medications had higher odds of medication nonadherence. Other risk factors for nonadherence included age years, dual beneficiaries receiving low income subsidy, and higher number of unique prescribers. Factors associated with lower odds of nonadherence included number of different medications filled and >1 physician office visits in the previous period. When examining the associations between medication nonadherence, and inpatient and ED use in Paper 2, we found that among elderly Medicare beneficiaries, nonadherence was significantly associated with a 57% increase in inpatient hospitalizations, and among non-elderly Medicare beneficiaries, nonadherence was significantly associated with 41% increase in inpatient stays and 25% increase in ED visits. Similar associations were found across all therapy classes examined (diabetes, cardiovascular, and COPD/asthma) in both age groups. However, nonadherence to diabetes and COPD/asthma drugs was not significantly associated with ED visits. Among other factors, mental illness, substance use disorder, non-Hispanic blacks and dual low-income subsidy status were associated with higher inpatient and ED use. Finally, the DID analyses in paper 3 showed that SafeMed Program did not improve medication adherence in vulnerable super-utilizers with chronic conditions. However, for some sub-group populations including Medicare only beneficiaries, patients >65 years of age, and patients with lower number of comorbidities, the intervention may have ensured that the decline in the probability of being adherent was not as low as it would have been in the absence of the intervention. Additionally, for patients diagnosed with COPD/asthma and diabetes, there were positive medication use trends in favor of enrollees, however, these associations were not statistically significant. CONCLUSIONS: This study is the first to our knowledge to demonstrate the magnitude and importance of medication nonadherence in vulnerable super-utilizers with chronic conditions. The study findings show that medication nonadherence is a significant problem among super-utilizers with chronic conditions and is associated with high inpatient and ED utilization. Furthermore, the findings suggest that medication management interventions during care transitions may not be sufficient for these high-risk patients and other alternative strategies such as addressing social risk factors, and removing cost barriers may be needed to improve adherence, especially among low-income dual beneficiaries, Medicaid enrollees, and patients with higher comorbidity.