Multiple patient comorbidities and environmental factors increase the risk of incisional wound complications. The literature suggests that negative pressure therapy (NPT) on clean closed surgical incisions may help reduce the risk of wound infections and other complications. In this case study, NPT was applied in the operating room to clean closed surgical wounds in four high-risk patients (two men, two women) following coronary artery bypass grafting using bilateral internal mammary arteries, transmetatarsal amputation, and abdominal hysterectomy. All wounds healed well. These results and currently available information suggest that prospective, randomized, controlled clinical studies to assess the safety, efficacy, and cost-effectiveness of NPT in the prevention of postoperative wound complications are warranted. In addition, if studies confirm the validity and reliability of the proposed patient grading system discussed, it may help guide use of NPT in postsurgical patients.