Background <p>Heart failure with preserved ejection fraction (HFpEF) is a multifaceted clinical condition that comprises nearly 50% of all heart failure cases, making it a significant clinical challenge. Qishen granule (QSG) is a promising traditional Chinese medicine (TCM) treatment that shows cardioprotective potential against chronic heart failure, as evidenced in previous studies. This trial intends to perform a prospective clinical study to observe the efficacy and safety of QSG on HFpEF.</p> Methods <p>This is a multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial. Eighty eligible participants with HFpEF will be enrolled and randomly assigned in a 1:1 ratio and receive either the QSG treatment or placebo for 12 weeks, with all participants maintaining guideline-directed HFpEF therapy throughout the study period. The primary outcomes are changes in peak VO₂ measured by cardiopulmonary exercise testing (CPET), and plasma NT-proBNP level from baseline to endpoint. Secondary outcomes include changes in echocardiography parameters, serum soluble human growth stimulation expressed gene 2 (ST2) protein levels, TCM syndrome integral scale score, quality of life and other indicators in CPET. Safety indicators like blood tests of liver and renal function and adverse events are used to assess the safety of QSG.</p> Discussion <p>This study’s result may establish clinical evidence supporting QSG’s therapeutic benefits and safety in HFpEF management.</p> Trial registration <p><a href="https://clinicaltrials.gov/">https://clinicaltrials.gov/</a>. Registration number: NCT06377761. Registered on 2 June 2022.</p>