Background: In cardiac surgery patients, post-sternotomy mediastinitis, also known as deep sternal wound infection (DSWI), is a major cause of postoperative morbidity and mortality. Negative pressure wound therapy (NPWT), also known as vacuum assisted closure (VAC) dressing, is one therapeutic alternative that offers the following advantages: regulation of fluid drainage, reduction of local edema, and bacterial load reduction, and early development of granulation tissue by angiogenic stimulation. By acting topically with a low complication rate, offering greater comfort to the medical team and patient, and reducing hospitalization time, antibiotic usage, and dressing changes, this therapy has become an important and efficient method for fighting infection in complex wounds. Objective: To evaluate the effectiveness and clinical outcome of vacuum‑assisted closure (VAC) therapy in the treatment of post-sternotomy mediastinitis in comparison with conventional treatment. Patients and methods: This study was conducted in National Heart Institute (NHI), Egypt. Patients were hospitalized from March 2019 to March 2020. It included patients with post-sternotomy mediastinitis treated with conventional therapy and VAC divided in two groups each group contained 30 patients. Results: The duration of VAC therapy was 7.42±2.23 days. Mean hospital stay after VAC therapy was 12.18±1.92 days. Twenty-two (92%) patients were treated successfully. At the end of VAC therapy, the mean reduction in wound size was 31.7%. The mean granulation tissue formation was 59%. Conclusion: VAC is a safe, reliable, and relatively new option for the treatment of DSWI after cardiac surgery. VAC is an alternative to conventional treatment in wound healing strategy in post-sternotomy mediastinitis.