Streptococcus milleri mediastinitis had resolved in a 44-year-old male after 3 weeks of combined parenteral antibiotic therapy including clindamycin, which showed the greatest in vitro activity against S. milleri isolated from this patient, and surgical drainage. This case demonstrates that primary purulent mediastinitis may be caused by a strain of S. milleri with or without other bacterial species, and suggests that S. milleri should be added to the list of causative organisms of purulent mediastinitis even when the patient has not undergone a surgical procedure.