"Culture-negative" wound infection and mediastinitis secondary to Mycoplasma hominis have been reported after cardiothoracic surgery but no case cluster has ever been described. We report 4 cases of infection in 3 cardiac and 1 bilateral sequential lung transplant recipient over 3 weeks of hospitalization. Successful treatment was achieved with early aggressive surgical intervention and combination antibiotics of clindamycin, doxycycline and/or ciprofloxacin. This cluster raises the question of nosocomial transmission of infection and supports a recommendation for single-room isolation and universal precautions for infected individuals.