Introduction Enoxaparin dosed by an anti-Xa trough level is effective at reducing venous thromboembolism (VTE) in trauma patients. We identified the patient characteristics associated with higher enoxaparin dosing based on anti-Xa trough levels. Methods A retrospective review was conducted on trauma patients admitted between August 2014 and February 2018 who received enoxaparin dosed by the anti-Xa trough level. Patients who received enoxaparin < 50 mg every 12 hours were compared to those who required >= 50 mg every 12 hours. Results Of the 246 patients included, 32 (13.0%) required enoxaparin >= 50 mg every 12 hours to achieve the prophylactic trough level. Factors associated with a higher dose of enoxaparin were male (96.8% vs. 3.2%, P < .01), younger age (39.5 vs. 52.7 years, P < .01), higher creatinine clearance (CrCl) (125.9 vs. 93.7 mL/min, P < .01), higher body surface area (2 m(2) vs. 1.8 m(2), P < .01), and higher injury severity score (18.4 vs. 10.8, P < .01). Height, weight, and body mass index were not significant factors. On regression analysis, CrCl was the only independent predictor for higher enoxaparin dose. There was an increased deep venous thrombosis rate in the higher dose cohort (12.5% vs. 0, P < .01) but no significant differences in transfusion rates. Conclusion Trauma patients who require higher enoxaparin doses to achieve prophylactic anti-Xa trough levels have a higher CrCl. Patients with high CrCl may benefit from an initial higher dose of enoxaparin to achieve a target anti-Xa level in a shorter time interval to decrease VTE risk.