Currently, the issue of chronic heart failure (CHF) is increasingly relevant in Kazakhstan, with a significantly higher mortality rate from the terminal stage of CHF, especially among patients in FC III-IV. Heart transplantation is considered the “gold” standard for surgical treatment of terminal CHF; however, endomyocardial biopsy, used for monitoring the transplanted heart, is an invasive and inconvenient procedure. This study explores the potential of safe and accurate monitoring of acute transplant rejection using circulating donor-derived cell-free DNA (dd-cfDNA). The study involved 40 patients who had undergone heart transplantation. The results revealed that 60% of them had undergone repeat surgery, while 40% had undergone primary transplantation. The primary causes of terminal CHF included various cardiomyopathies, predominantly dilated and ischemic. The dd-cfDNA method shows promise in differentiating T-cell-mediated (ACR) and antibody-mediated (AMR) rejection, with distinct patterns of dd-cfDNA elevation. These differences have high clinical significance for diagnosis and treatment strategies. However, despite the prospects of using dd-cfDNA, further research is needed to establish threshold values and confirm its effectiveness in clinical practice. The study also raises important questions about the cost and accessibility of the method, requiring additional attention in the development of precision medicine methods in the field of heart transplantation.