OBJECTIVE:Disease management programs (DMPs) may reduce short-term readmission or death after heart failure (HF) hospitalization. We sought to determine if targeting of DMP to the highest-risk patients could improve efficiency. METHODS AND RESULTS:Patients (n = 412) admitted with HF were randomized to usual care or an intensive DMP including optimizing intravascular volume status at discharge, increased self-care education, exercise guidance, closer home surveillance, and increased intensity of HF nurse follow-up. Both treatment groups were similar in demographics, medication use, Charlson comorbidity index, ejection fraction, and left ventricular and atrial volumes. Readmission or death occurred in 74/197 (37%) usual care and 50/215 (23%) DMP patients within 30 days (relative risk [RR] 0.62, 95% confidence interval [CI] 0.46-0.84), and 113/197 (57%) usual care and 78/215 (36%) DMP patients within 90 days, (RR 0.63, 9%% CI 0.51-0.78). The predicted risk of death and readmission (estimated from our previously developed risk score) was similar between treatment groups (mean predicted risk 38.6 ± 22.2% vs 39.4 ± 21.9%; P = .73) and similar across categories of predicted risk between the treatment groups. For 30-day readmission or death, patients from the 2 highest risk quintiles showed a benefit from intervention, and there was an interaction between intervention and predicted risk (P = .02). For 90-day readmission or death, most patients-other than those in the lowest-risk quintile-benefited from the intervention. CONCLUSIONS:Use of a risk score may permit targeting of DMP to reduce HF admission. Intensive DMP may reduce short-term readmission or death, particularly in high-risk patients.