Negative-pressure wound therapy (NPWT) has been used for the treatment of deep sternal wound infection (DSWI) with promising results. However, questions have been raised regarding the potential risk of right ventricle (RV) rupture during treatment. In the present study, we evaluate our clinical experience of NPWT focusing on RV rupture and major bleeding complications and its potentially negative impact on 30-day mortality during an 11-year period. Serious bleeding complications during NPWT were reviewed for 176 patients treated for DSWI between January 1999 and April 2010. The 30-day mortality following DSWI was 1.1% (2/176). Four patients (2.3%) suffered bleeding from the RV rupture during NPWT of the sternal wound (two spontaneous and two debridement related). Furthermore, two patients had debridement-related bleedings from the venous bypass grafts during wound dressing change. The very low 30-day mortality (1.1%) following DSWI supports the use of NPWT. Overall, even if major bleeding complications may occur, the risk of RV rupture seems to be outweighed by the benefit of superior infection control. However, surgical experience is recommended when debriding sternal wounds and we recommend the use of a wound dressing, such as paraffin gauze, in order to protect the RV from direct contact with the polyurethane foam.