Introduction: Median sternotomy is the most preferred approach in heart surgery. Post-sternotomy mediastinitis is a catastrophic and potentially life-threatening complication with an incidence rate of 0.15% to 5%, and its overall mortality rate reaches 47%. In this study, we aimed to compare the results of vacuum-assisted closure technique and the conventional methods on the management of mediastinitis following isolated coronary artery bypass graft surgery. Methods: Between February 2001 and July 2013, 32,106 patients who underwent cardiac operations were evaluated retrospectively. One hundred and fourteen patients who developed post-sternotomy mediastinitis were included in this study. The patients were divided into two groups and compared — vacuum-assisted closure group (n=52, 45.6%) and conventional treatment group (n=62, 54.4%). Results: There were no differences between the two groups according to the patients’ characteristics, surgical data, and mediastinal cultures. However, we found that total treatment duration for post-sternotomy mediastinitis, time interval from diagnosis to negative culture, hospitalization time, and in-hospital mortality were statistically significantly lower in the vacuum-assisted closure group than in the conventional treatment group (P<0.001, P<0.001, P<0.001, and P=0.03, respectively). Conclusion: This study demonstrates that the vacuum-assisted closure technique improves the medical outcome of patients with post-sternotomy mediastinitis compared with the conventional treatment. The vacuum-assisted closure is a safe and more effective treatment modality for patients with post-sternotomy mediastinitis after cardiac surgery with reasonable morbidity and mortality.