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To determine the safety of early enoxaparin for venous thromboembolism (VTE) prophylaxis in patients with blunt traumatic brain injury (TBI).Prospective observational study of patients with TBI who received enoxaparin within 48 hours after admission. Brain computed tomography (CT) scans were obtained at the time of admission, at 24 hours, and at variable intervals thereafter based on clinical course. Patients were excluded from the study for intracerebral contusions ≥2 cm, multiple contusions within one brain region, subdural or epidural hematomas ≥8 mm, increased size or number of lesions on follow-up CT, persistent intracranial pressure >20 mm Hg, or neurosurgeon or trauma surgeon reluctance to initiate early pharmacologic VTE prophylaxis. Bleeding complications were defined as CT progression of hemorrhage by Marshall CT Classification or radiologists’ report, regardless of any neurologic deterioration. Main outcomes measured were intracranial bleeding complications, discharge Glasgow Outcome Score, and hospital mortality.Five hundred twenty-five patients were studied. Eighteen patients (3.4%) had progressive hemorrhagic CT changes after receiving enoxaparin, 12 of whom had no change in treatment, neurologic status, or outcome. Six patients (1.1%) had a change in treatment or potential outcome, including three who required subsequent craniotomy. Twenty-one patients (4.0%) died, and pharmacologic prophylaxis may have contributed to one death (0.2%). Discharge Glasgow Outcome Scores were 445 (84.8%) good recovery, 19 (3.6%) moderate disability, 36 (6.8%) severe disability, 4 (0.8%) persistent vegetative state, and 21 (4.0%) dead.Enoxaparin should be considered as an option for early VTE prophylaxis in selected patients with blunt TBI. Early enoxaparin should be strongly considered in those patients with TBI with additional high risk traumatic injuries.