Aspergillus fumigatus is an opportunistic fungus that mainly affects immunocompromised patients. Due to significant immunosuppressive therapy, patients who undergo orthotopic heart transplant have an increased risk of infection. Aspergillosis is the most common fungal infection in orthotopic heart transplant recipients (70%) and usually presents as invasive aspergillosis, which has a rapidly progressive course and is highly fatal. In heart transplant patients with invasive aspergillosis, overall mortality may range from 53% to 78%. Aspergillus mediastinitis infection is somewhat rare in orthotopic heart transplant recipients, with only 6 reported cases. Treatment may require early surgical drainage and antifungal therapy. We present the case of a 50-year-old man who developed Aspergillus mediastinitis 1 year after heart transplant surgery. This case illustrates the diagnostic challenge of an atypical presentation of Aspergillus mediastinitis and the importance of multiple drainage procedures in refractory disease, combined with long-term antifungal therapy.