OBJECTIVES: To evaluate the impact of negative pressure wound therapy (NPWT) after severe open fractures on deep infection. DESIGN: Prospective randomized study. SETTING: Academic level I trauma center. PATIENTS/PARTICIPANTS: Fifty-nine patients with 63 severe high-energy open fractures were enrolled in this study, with data available on 58 patients with 62 open fractures. INTERVENTION: Twenty-three patients with 25 fractures randomized to the control group and underwent initial irrigation and debridement followed by standard fine mesh gauze dressing, with repeat irrigation and debridement every 48-72 hours until wound closure. Thirty-five patients randomized to the NPWT group and had identical treatment except that NPWT was applied to the wounds between irrigation and debridement procedures until closure. MAIN OUTCOME MEASUREMENTS: The presence or absence of deep wound infection or osteomyelitis, wound dehiscence, and fracture union were primary outcome measures. RESULTS AND CONCLUSIONS: Control patients developed 2 acute infections (8%) and 5 delayed infections (20%), for a total of 7 deep infections (28%), whereas NPWT patients developed 0 acute infections, 2 delayed infections (5.4%), for a total of 2 deep infections (5.4%). There is a significant difference between the groups for total infections (P = 0.024). The relative risk ratio is 0.199 (95% confidence interval: 0.045-0.874), suggesting that patients treated with NPWT were only one-fifth as likely to have an infection compared with patients randomized to the control group. NPWT represents a promising new therapy for severe open fractures after high-energy trauma.