BACKGROUND: Many health systems have implemented team-based programs to improve transitions from hospital to home for high-need, high-cost patients. While preliminary outcomes are promising, there is limited evidence regarding the most effective strategies. OBJECTIVE: To determine the effect of an intensive interdisciplinary transitional care program emphasizing medication adherence and rapid primary care follow-up for high-need, high-cost Medicaid and Medicare patients on quality, outcomes, and costs. DESIGN: Quasi-experimental study. PATIENTS: Among 2235 high-need, high-cost Medicare and Medicaid patients identified during an index inpatient hospitalization in a non-profit health care system in a medically underserved area with complete administrative claims data, 285 participants were enrolled in the SafeMed care transition intervention, and 1950 served as concurrent controls. INTERVENTIONS: The SafeMed team conducted hospital-based real-time screening, patient engagement, enrollment, enhanced discharge care coordination, and intensive home visits and telephone follow-up for at least 45 days. MAIN MEASURES: Primary difference-in-differences analyses examined changes in quality (primary care visits, and medication adherence), outcomes (preventable emergency visits and hospitalizations, overall emergency visits, hospitalizations, 30-day readmissions, and hospital days), and medical expenditures. KEY RESULTS: Adjusted difference-in-differences analyses demonstrated that SafeMed participation was associated with 7% fewer hospitalizations (- 0.40; 95% confidence interval (CI), - 0.73 to - 0.06), 31% fewer 30-day readmissions (- 0.34; 95% CI, - 0.61 to - 0.07), and reduced medical expenditures ($- 8690; 95% CI, $- 14,441 to $- 2939) over 6 months. Improvements were limited to Medicaid patients, who experienced large, statistically significant decreases of 39% in emergency department visits, 25% in hospitalizations, and 79% in 30-day readmissions. Medication adherence was unchanged (+ 2.6%; 95% CI, - 39.1% to 72.9%). CONCLUSIONS: Care transition models emphasizing strong interdisciplinary patient engagement and rapid primary care follow-up can enable health systems to improve quality and outcomes while reducing costs among high-need, high-cost Medicaid patients.