Background: Major trauma is a risk factor for venous thromboembolism (VTE). Trauma guidelines recommend prompt initiation of pharmacologic VTE prophylaxis. While early initiation is recommended, delays in therapy can occur. Objective: The aim of this study was to evaluate the compliance of pharmacologic VTE prophylaxis initiation timing with trauma guidelines and impact on rates of VTE, bleeding and in-hospital mortality. Methods: This retrospective cohort study included patients admitted to a trauma unit between January 1, 2020 and December 1, 2021. Patients were stratified by injury type and categorized as either compliant or non-compliant based on timing of initiation. Rates of VTE, bleeding, and in-hospital mortality were collected. Results: Of the 300 patients, 259 (86.3%) were compliant. Reasons for non-compliance included bleeding (19.5%) and pending evaluation for intervention such as nerve block procedure (12.2%) and surgical operation (4.9%). There were no differences in VTE (4.8% vs 1.2%, P = .139) or bleeding (4.6% vs 0%, P = N/A) between groups. There was a higher rate of in-hospital mortality in the non-compliant group (12.2% vs 2.3%, P = .009). Upon multivariate logistic regression, the ICU setting was identified as a risk factor for noncompliance ( P = .020, OR = .45). Conclusion: Initiating pharmacologic VTE prophylaxis in concordance with trauma guidelines led to low observed rates of VTE and bleeding. In evaluating reasons for noncompliance, we identified areas of improvement for initiation including minimizing inappropriate delays in therapy.