Background <p><i>Ureaplasma urealyticum</i>, a commensal organism, is potentially pathogenic. In solid organ transplant recipients, non-genitourinary <i>U. urealyticum</i> infection is associated with an increased risk of graft failure or death.</p> Results <p>We reported a case of mediastinitis caused by <i>U. urealyticum</i> in a heart transplant recipient and reviewed 13 other cases previously described. Among the 14 patients, 3 were female and 11 were male, with a median age of 61 years. The median time to symptom onset was 9 days after surgery. Among the 10 documented cases with reported symptoms, altered mental status and hyperammonemia syndrome occurred in 9 cases, whereas our patient manifested persistent fever. Both culture and molecular diagnostics were employed in the reviewed cases, with molecular methods predominating. <i>U. urealyticum</i> was difficult to cover with initial empirical antibiotic therapy; the patient in this study improved after omadacycline antimicrobial therapy and was successfully discharged following subsequent management. Regarding clinical outcomes, four patients died or withdrew from treatment, while targeted therapy duration among surviving patients ranged from 9 days to 4 weeks.</p> Conclusions <p>There is a possibility of severe <i>U. urealyticum</i> infection in patients with immunodeficiency after organ transplantation. Monitoring ammonia levels, utilizing rapid diagnostics, and initiating prompt treatment are all crucial to improving prognosis and reducing severe nerve damage, organ dysfunction, and mortality.</p> Clinical trial number <p>Not applicable.</p>