Case management (CM) is an important strategy for chronic disease care. By utilizing non-physician providers for conditions requiring ongoing care and follow-up, CM can facilitate guideline-concordant care, patient empowerment, and improvement in quality of life. We identify a series of critical factors required for successful CM implementation. Heart to Heart is a clinical trial evaluating CM for coronary heart disease (CHD) risk reduction in a multiethnic, low-income population. Patients at elevated cardiac risk were randomized to CM plus primary care (212 patients) or to primary care alone (207). Over a mean follow-up of 17 months, patients received face-to-face nurse and dietitian visits. Mean contact time was 14 hours provided at an estimated cost of $1250 per patient for the 341 (81%) patients completing follow-up. Visits emphasized behavior change, risk-factor monitoring, self-management skills, and guideline-based pharmacotherapy. A statistically significant reduction in mean Framingham risk probability occurred in CM plus primary care relative to primary care alone (1.6% decrease in 10-year CHD risk, p = 0.007). Favorable changes were noted across individual risk factors. Our findings suggest that successful CM implementation relies on choosing appropriate case managers and investing in training, integrating CM into existing care systems, delineating the scope and appropriate levels of clinical decision making, using information systems, and monitoring outcomes and costs. While our population, setting, and intervention model are unique, these insights are broadly relevant. If implemented with attention to critical factors, CM has great potential to improve the process and outcomes of chronic disease care.