The purpose of this study is to evaluate the effect of Negative Pressure Wound Therapy (NPWT) on closed surgical incisions. We performed a prospective randomized controlled clinical trial comparing NPWT to standard dry dressings on surgical incisions. Patients presenting to a high-volume wound center were randomized to receive either a V.A.C. (KCI, San Antonio, TX) or a standard dry dressing over their incision at the conclusion of surgery. These were primarily high-risk patients with multiple comorbidities. The 2 groups were compared, and all incisions were evaluated for infection and dehiscence postoperatively. Eighty-one patients were included for analysis. Thirty-seven received dry dressings, and 44 received NPWT. Seventy-four of these underwent lower extremity wound closure. Average follow-up was 113 days. There were no differences in demographic, preoperative, and operative variables between groups; 6.8% of the NPWT group and 13.5% of the dry dressing group developed wound infection, but this was not statistically significant (P = 0.46). There was no difference in time to develop infection between the groups. There was no statistical difference in dehiscence between NPWT and dry dressing group (36.4% vs 29.7%; P = 0.54) or mean time to dehiscence between the 2 groups (P = 0.45). Overall, 35% of the dry dressing group and 40% of the NPWT group had a wound infection, dehiscence, or both. Of these, 9 in the NPWT group (21%) and 8 in the dry dressing group (22%) required reoperation. There is a significant rate of postoperative infection and dehiscence in patients with multiple comorbidities. There was no difference in the incidence of infection or dehiscence between the NPWT and dry dressing group. This study is registered with ClinicalTrials.gov. The unique registration number is NCT01366105.