Introduction. Thoracic aortic graft infection is a rare complication after cardiac surgery with no consensus having been reached on the most appropriate type of management. Although most commonly caused by gram-positive cocci, aortic graft infection by Mycoplasma hominis can occur. Case Report. A 63-year-old male patient with an aneurysm of the ascending aorta was admitted to the authors’ institution for surgical treatment. A replacement of the ascending aorta with a polyester vascular graft was performed using a valve-sparing aortic valve reimplantation technique. During postoperative course, the patient became septic with a spiking fever and elevated inflammatory markers. A computed tomography scan revealed signs of mediastinitis. M hominis was identified in blood cultures and intraoperative tissue samples. An antibiogram-based antibiotic solution (tigecycline in 5% glucose solution) was instilled twice daily into the thoracic cavity using negative pressure wound therapy with instillation and dwell time for 8 days. This type of management allowed the authors to avoid graft replacement, and good midterm outcomes were achieved. Conclusions. To the authors’ best knowledge, this is the first described successful treatment of an aortic graft infection caused by M hominis without a surgical removal of the prosthetic material using antibiotic irrigation.