BACKGROUND: Venous thromboembolism is a major patient safety issue. The Plastic Surgery Foundation-sponsored Venous Thromboembolism Prevention Study examined whether postoperative enoxaparin prevents symptomatic venous thromboembolism in adult plastic surgery patients. METHODS: In 2009, four sites uniformly adopted a clinical protocol. Patients with a Caprini score of 3 or higher received postoperative enoxaparin prophylaxis for the duration of inpatient stay. Venous Thromboembolism Prevention Study historical control patients had an operation between 2006 and 2008 but received no chemoprophylaxis for 60 days after surgery. The primary study outcome was symptomatic 60-day venous thromboembolism. RESULTS: Three thousand three hundred thirty-four patients (1876 controls and 1458 enoxaparin patients) were included. Notable risk reduction was present in patients with a Caprini score greater than 8 (8.54 percent versus 4.07 percent; p=0.182) and a Caprini score of 7 to 8 (2.55 percent versus 1.15 percent; p=0.230) who received postoperative enoxaparin. Logistic regression was limited to highest risk patients (Caprini score>/=7) and demonstrated that length of stay greater than or equal to 4 days (adjusted odds ratio, 4.63; p=0.007) and Caprini score greater than 8 (odds ratio, 2.71; p=0.027) were independent predictors of venous thromboembolism. When controlling for length of stay and Caprini score, receipt of postoperative enoxaparin was protective against venous thromboembolism (odds ratio, 0.39; p=0.042). CONCLUSIONS: In high-risk plastic surgery patients, postoperative enoxaparin prophylaxis is protective against 60-day venous thromboembolism when controlling for baseline risk and length of stay. Hospitalization for 4 or more days is an independent risk factor for venous thromboembolism. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.