Background: The use of low-molecular-weight heparin (LMWH) for the chemoprophylaxis of venous thromboembolism (VTE) in trauma patients is supported by Level-1 evidence. Because Enoxaparin was the agent used in the majority of studies for establishing the efficacy of LMWH in VTE, it remains unclear if Dalteparin provides an equivalent effect. Objective: To compare Dalteparin to Enoxaparin and investigate their equivalence as VTE prophylaxis in trauma. Patients/setting: Trauma patients receiving VTE chemoprophylaxis in the Surgical Intensive Care Unit of a Level-1 Trauma Center from 2009 (Enoxaparin) to 2010 (Dalteparin) were included. Measurements: The primary outcome was the incidence of clinically significant VTE. Secondary outcomes included heparin-induced thrombocytopenia (HIT), major bleeding, and drug acquisition cost savings. Equivalence margins were set between -5 and 5 %. Main results: A total of 610 patient records (277 Enoxaparin, 333 Dalteparin) were reviewed. The two study groups did not differ significantly: blunt trauma 67 vs. 62 %, p = 0.27; mean Injury Severity Score (ISS) 17 ± 10 vs. 16 ± 10, p = 0.34; Acute Physiology and Chronic Health Evaluation (APACHE) II score 17 ± 9 vs. 17 ± 10, p = 0.76; time to first dose of LMWH 69 ± 98 vs. 65 ± 67 h, p = 0.57). The rates of deep venous thrombosis (DVT) (3.2 vs. 3.3 %, p = 1.00), pulmonary emboli (PE) (1.8 vs. 1.2 %, p = 0.74), and overall VTE (5.1 vs. 4.5 %, p = 0.85) did not differ. The absolute difference in the incidence of overall VTE was 0.5 % [95 % confidence interval (CI): -2.9, 4.0 %, p = 0.85]. The 95 % CI was within the predefined equivalence margins. There were no significant differences in the frequency of HIT or major bleeding. The total year-on-year cost savings, achieved with 277 patients during the switch to Dalteparin, was estimated to be $107,778. Conclusions: Dalteparin is equivalent to Enoxaparin in terms of VTE in trauma patients and can be safely used in this population, with no increase in complications and significant cost savings. © 2013 Springer-Verlag Berlin Heidelberg.