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Pulmonary embolism (PE) is a leading cause of delayed mortality in patients with severe injury. While low-molecular-weight heparin (LMWH) is often favored over unfractionated heparin (UH) for thromboprophylaxis, evidence is lacking to demonstrate an effect on the occurrence of PE. This study compared the effectiveness of LMWH versus UH to prevent PE in patients following major trauma.Data for adults with severe injury who received thromboprophylaxis with LMWH or UH were derived from the American College of Surgeons Trauma Quality Improvement Program (2012–2015). Patients who died or were discharged within 5 days were excluded. Rates of PE were compared between propensity-matched LMWH and UH groups. Subgroup analyses included patients with blunt multisystem injury, penetrating truncal injury, shock, severe traumatic brain injury, and isolated orthopedic injury. A center-level analysis was performed to determine if practices with respect to choice of prophylaxis type influence hospital PE rates.We identified 153,474 patients at 217 trauma centers who received thromboprophylaxis with LMWH or UH. Low-molecular-weight heparin was given in 74% of patients. Pulmonary embolism occurred in 1.8%. Propensity score matching yielded a well-balanced cohort of 75,920 patients. After matching, LMWH was associated with a significantly lower rate of PE compared with UH (1.4% vs. 2.4%; odds ratio, 0.56; 95% confidence interval, 0.50–0.63). This finding was consistent across injury subgroups. Trauma centers in the highest quartile of LMWH utilization (median LMWH use, 95%) reported significantly fewer PE compared with centers in the lowest quartile (median LMWH use, 39%; 1.2% vs. 2.0%; odds ratio, 0.59; 95% confidence interval, 0.48–0.74).Thromboprophylaxis with LMWH (vs. UH) was associated with significantly lower risk of PE. Trauma centers favoring LMWH-based prophylaxis strategies reported lower rates of PE. Low-molecular-weight heparin should be the anticoagulant agent of choice for prevention of PE in patients with major trauma.Therapeutic study, level III.