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We hypothesized that low molecular weight heparin (LMWH) is superior to unfractionated heparin (UH) for venous thromboembolism (VTE) prophylaxis in patients with severe traumatic brain injuries (TBI).Pharmacological VTE prophylaxis with LMWH or UH is the current standard of care in TBI. Clinical work suggests that LMWH may be more effective than UH for VTE prophylaxis in trauma patients. Experimental work shows that heparinoids may have neuroprotective properties.ACS TQIP database study including patients with blunt severe TBI (AIS ≥ 3), those that received LMWH or UH VTE prophylaxis. Patients with severe extracranial injuries (AIS ≥ 3), death within 72 hours, or hospital stay <48 hours were excluded. Demographic and clinical data on admission was collected, as well as head, thorax, and abdomen AIS, and timing of prophylaxis (within 48 hours, 49–72 hours, and >72 hours). Outcomes included VTE complications, mortality, and unplanned return to the operating room. Multivariate analysis was performed to compare outcomes between patients receiving LMWH and UH.Overall, 20,417 patients met the criteria for inclusion in the study, 10,018 (49.1%) received LMWH and 10,399 (50.9%) UH. Multivariate analysis showed that LMWH was an independent protective factor against mortality and thromboembolic complications, regardless of timing of prophylaxis initiation. The type of prophylaxis had no effect on the need for unplanned return to the operating room.LMWH prophylaxis in severe TBI is associated with better survival and lower thromboembolic complications than UH.