AimsThe long‐term cost‐effectiveness of MitraClip in heart failure patients with secondary mitral regurgitation is still unclear. This study aimed to evaluate the long‐term cost‐effectiveness of MitraClip added to guideline‐directed medical therapy vs. guideline‐directed medical therapy alone in heart failure patients with secondary mitral regurgitation from the perspective of the healthcare systems of mainland China, the United Kingdom, Germany, and the United States.Methods and resultsA two‐stage (decision + Markov) model was built. Health utilities were defined by the New York Heart Association class, heart failure re‐hospitalization, and death and were calculated based on the 5 year follow‐up results of the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation trial. Direct healthcare costs were derived from the nationally representative data. Future utilities and costs were discounted at country‐specific rates. The primary outcome was the lifetime incremental cost‐effectiveness ratio. The mean age of the base case in our model was 72.2 years. Over a lifetime horizon, treatment with MitraClip was associated with 829 fewer heart failure re‐hospitalizations per 1000 treated patients. The MitraClip treatment was associated with incremental quality‐adjusted life‐year gains of 0.71, 0.76, 0.78, and 0.78, as well as incremental cost‐effectiveness ratios of ¥468 462, £28 910, €26 045, and $71 199 per quality‐adjusted life‐year for a lifetime horizon in mainland China, the United Kingdom, Germany, and the United States, respectively. In probabilistic sensitivity analysis, 0.2%, 59.4%, 99.6%, and 84.7% of patients were cost‐effective in mainland China, the United Kingdom, Germany, and the United States at the country‐specific willingness‐to‐pay thresholds.ConclusionsMitraClip + guideline‐directed medical therapy was cost‐effective in heart failure patients with secondary mitral regurgitation in the United Kingdom, Germany, and the United States, but not in mainland China from the perspective of the national healthcare system.