Background <p>Heart failure with preserved ejection fraction (HFpEF) has a high prevalence and risk of mortality, which is still on the rise. Current drug therapies are ineffective, making the development of new drugs for HFpEF particularly important. Qifu Yixin prescription (QYP) has a 20-year history of treating HF, and we have observed positive clinical effects of QYP on HFpEF. However, high-level clinical evidence is lacking. Therefore, a standardized randomized controlled trial (RCT) is necessary to evaluate its clinical effectiveness and safety.</p> Methods and analysis <p>This study was a randomized, double-blind, placebo-controlled, single-center trial. Participants with HFpEF were randomized in a 1:1 ratio to either the QYP or placebo group for a period of 12 weeks, according to a random number table. The follow-up period lasted for 12 weeks after drug discontinuation. The primary outcome was the change in NYHA classification from baseline to 24 weeks. Secondary outcomes include changes in NT-proBNP, BNP, echocardiographic indices, traditional Chinese medicine symptomatic score scale (TCMSSS), 6-minute walk test (6MWT), Minnesota living with heart failure questionnaire (MLHFQ), Kansas City cardiomyopathy questionnaire (KCCQ), HF readmission rate, cardiovascular mortality, and composite outcomes to evaluate the clinical effectiveness of QYP in treating HFpEF. The safety of QYP will be evaluated through blood, urine, and stool routine tests, liver and kidney function assessments, electrolytes, and electrocardiograms.</p> Discussion <p>This study will provide standardized, high-quality evidence-based medical support for the clinical application of QYP and facilitate the development of new drugs for HFpEF.</p> Trial registration <p><a href="http://www.chictr.org.cn">http://www.chictr.org.cn</a>. Trial number: ChiCTR2400088641. Registered on 22 Aug 2024.</p>