OBJECTIVES: First, to investigate the prevalence and types of drug therapy problems and medication discrepancies among super-utilizers, and associated patient characteristics. Second, to examine the outcomes of pharmacist recommendations and estimated cost avoidance through care transitions support focused on medication management. DESIGN: Retrospective analysis of the pharmacist-led interventions as part of the SafeMed Program. SETTING: A large nonprofit health care system serving the major medically underserved areas in Memphis, Tennessee. PARTICIPANTS: Three hundred seventy-four super-utilizing SafeMed participants with multiple chronic conditions and polypharmacy. INTERVENTION: Comprehensive medication review, medication therapy management, enhanced discharge planning, home visits, telephone follow-up, postdischarge medication reconciliation, and care coordination with physicians. MAIN OUTCOME MEASURES: Types of drug therapy problems, outcomes of pharmacist recommendations, estimated cost avoided, medication discrepancies, and self-reported medication adherence. RESULTS: Prevalence of drug therapy problems and postdischarge medication discrepancies was 80.7% and 75.4%, respectively. The most frequently occurring drug therapy problems were enrollee not receiving needed medications (33.4%), underuse of medications (16.9%), and insufficient dose or duration (11.2%). Overall 50.8% of the pharmacist recommendations were accepted by physicians and patients, resulting in an estimated cost avoidance of $293.30 per drug therapy problem identified. Multivariate analysis indicated that participants with a higher number of comorbidities were more likely to have medication discrepancies (odds ratio 1.23 [95% CI 1.05-1.44]). Additional contributors to postdischarge medication discrepancies were difficulty picking up and paying for medications and not being given necessary prescriptions before discharge. CONCLUSION: Drug therapy problems and medication discrepancies are common in super-utilizers with multiple chronic conditions and polypharmacy during transitions of care, and greater levels of comorbidity magnify risk. Pharmacist-led interventions in the SafeMed Program have demonstrated success in resolving enrollees' medication-related issues, resulting in substantial estimated cost savings. Preliminary evidence suggests that the SafeMed model's focus on medication management has great potential to improve outcomes while reducing costs for vulnerable super-utilizing populations nationwide.