Background: Published studies have generated mixed, controversial results regarding the Cost-effectiveness of heart failure disease management programs (HF-DMPs). This study assessed the cost-effectiveness of an HF-DMP in ambulatory patients compared with usual care (UC). Methods: In the prospective randomized REMADHE trial, we evaluated incremental costs per quality adjusted life-year (QALY) and life-year (LY) gained as effectiveness ratios (ICERs) over a study period of 2.47 +/- 1.75 years. Results: The REMADHE HF-DMP was more effective and less costly than UC in terms of both QALYs and LYs (95% and 55% chance of dominance, respectively). Average saving was US$7345 (2.5%-97.5% bootstrapped confidence interval similar to 16,573 to +921). The chance of DMP being cost-effective at a willingness to pay US$10,000 per QALY or LY was 99% and 96%, respectively. Cost-effectiveness of HF-DMP was highest in subgroups with left ventricular ejection fraction <35%, age >50 years, male sex, New York Heart Association (NYHA) functional class >= III, and ischemic etiology. The chance of DMP being cost-effective at a willingness to pay US$10,000 per QALY was >= 90% in all subgroups apart from NYHA functional class I-II, where it was 70%. Even when the intervention costs increased by 500% or when excluding outliers in costs, DMP had a high chance of being cost-effective (87%-99%). Conclusions: The HF-DMP of the REMADHE trial, which encompasses long-term repeated education alongside telephone monitoring, has a high probability of being cost-effective in ambulatory patients with HF.