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Consensus guidelines support the use of low-molecular-weight heparin for venous thromboembolism (VTE) prophylaxis in high-risk trauma patients but do not recommend a specific regimen. The current study compared the effectiveness and safety of enoxaparin 40 mg once-daily versus enoxaparin 30 mg twice-daily for VTE prophylaxis in high-risk trauma patients.A retrospective chart review was conducted of all trauma patients older than 18 years of age admitted to Shands at the University of Florida between July 1, 2005 and June 30, 2007, who received either dosing regimen. Excluded were patients with Injury Severity Score <9, surviving <2 days, hospital length of stay <2 days, receipt of >1 agent, and/or dosing regimen for VTE prophylaxis during hospitalization, interruption in therapy, pregnancy, or diagnosis of a VTE within 24 hours of admission.A total of 409 patients were treated with once-daily dosing and 278 patients were treated with twice-daily dosing. The overall rate of VTE was 2.9% (95% confidence interval, 1.52, 5.07) in the once-daily group and 1.1% in the twice-daily group (95% confidence interval, 0.22, 3.12; P = .118). Major bleeding occurred in 11 patients in the once-daily group and 5 patients in the twice-daily group (1.8% vs 2.7%; P = .608).Enoxaparin 30 mg twice-daily may be more effective than enoxaparin 40 mg once-daily for prevention of VTE in high-risk trauma patients; however, statistical significance was not achieved. There were no statistically significant differences observed in clinically significant bleeding. Further study is needed to clarify which dosing regimen of enoxaparin is superior with regard to safety and effectiveness.