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Chagas disease is caused by the parasite Trypanosoma cruzi (TC), transmitted via insect vectors most commonly found in Mexico, Central America, and South America, with ∼8 million current active cases. Heart transplantation (HT) can be lifesaving in patients developing severe cardiomyopathy due to Chagas cardiomyopathy (CC), with comparable survival to HT performed for other indications. However, patients are at risk for Chagas disease reactivation (CDR) as a consequence of immunosuppression following transplantation. Failure to identify CDR has been associated with severe or fatal outcomes. Herein, we describe a patient with a history of CC who underwent dd-cfDNA testing for rejection surveillance post HT. A retrospective case report of a HT patient with a history of Chagas disease who was monitored for HT rejection using dd-cfDNA analysis using the ProsperaTM test (Natera Inc, Austin, TX). This is a 44 y/o Hispanic male post HT 11/25/2022 (Figure 1). The patient was diagnosed with non-ischemic cardiomyopathy (NICM) in 2021 with an unclear etiology, however, reported "heart infection" at age 17 which was treated with antibiotics while living in El Salvador. Perioperative to HT, concomitant viral symptoms triggered an infectious disease consult. The patient was found to be positive for IgG TC antibodies while TC PCR was initially negative. The patient was treated with antibiotic therapies and the viral symptoms resolved. A stable postoperative course ensued. The patient underwent dd-cfDNA testing for rejection surveillance starting ∼1 month post HT. Rising trends in dd-cfDNA levels, above the patient's baseline dd-cfDNA% results (0.08%), and in one case above the 0.15% threshold for HT rejection risk, were noted between March and May 2023 (∼8 months post HT). However, there were no clinical/diagnostics suggestive for HT rejection. Notably, during this timeframe of rising dd-cfDNA%, a pre-scheduled followup of PCR testing for TC, came back positive. The patient remained asymptomatic and immunosuppressant regimen was modified; ultimately both dd-cfDNA% and TC PCR quiesced. Transplant programs in the United States are being encouraged to implement a monitoring program for HT recipients with Chagas disease. This case suggests that the elevation of dd-cfDNA may have been a harbinger of CDR, however whether it was detecting Chagas related allograft injury is unknown. More research is needed on preemptive approaches for monitoring Chagas disease reactivation in patients undergoing HT. [ABSTRACT FROM AUTHOR]