Mycoplasma hominis infections are easily missed because conventional methods for bacterial detection may fail. Here, 8 cases of septic mediastinitis due to M. hominis are reported and reviewed in the context of previously reported cases of mediastinitis, sternum wound infection, pleuritis, or pericarditis caused by M. hominis. All 8 patients had a predisposing initial condition related to poor cardiorespiratory function, aspiration, or complications related to coronary artery surgery or other thoracic surgeries. Mediastinitis was associated with purulent pleural effusion and acute septic symptoms requiring inotropic medication and ventilatory support. Later, the patients had a tendency for indolent chronic courses with pleuritis, pericarditis, or open sternal wounds that lasted for several months. M. hominis infections may also present as mild sternum wound infection or as chronic local pericarditis or pleuritis without septic mediastinitis. Treatment includes surgical drainage and debridement. Antibiotics effective against M. hominis should be considered when treating mediastinitis of unknown etiology.