BACKGROUND The incidence of venous thromboembolism (VTE) without prophylaxis is as high as 80% after major trauma. Initiation of prophylaxis is often delayed because of concerns of injury-associated bleeding. As the effect of delays in the initiation of prophylaxis on VTE rates is unknown, we set out to evaluate the relationship between late initiation of prophylaxis and VTE. METHODS Data were derived from a multicenter prospective cohort study evaluating clinical outcomes in adults with hemorrhagic shock after injury. Analyses were limited to patients with an Intensive Care Unit length of stay >or=7 days. The rate of VTE was estimated as a function of the time to initiation of pharmacologic prophylaxis. A multivariate stepwise logistic regression model was used to evaluate factors associated with late initiation. RESULTS There were 315 subjects who met inclusion criteria; 34 patients (11%) experienced a VTE within the first 28 days. Prophylaxis was initiated within 48 hours of injury in 25% of patients, and another one-quarter had no prophylaxis for at least 7 days after injury. Early prophylaxis was associated with a 5% risk of VTE, whereas delay beyond 4 days was associated with three times that risk (risk ratio, 3.0, 95% CI [1.4-6.5]). Factors associated with late (>4 days) initiation of prophylaxis included severe head injury, absence of comorbidities, and massive transfusion, whereas the presence of a severe lower extremity fracture was associated with early prophylaxis. CONCLUSIONS Clinicians are reticent to begin timely VTE prophylaxis in critically injured patients. Patients are without VTE prophylaxis for half of all days within the first week of admission and this delay in the initiation of prophylaxis is associated with a threefold greater risk of VTE. The relative risks and benefits of early VTE prophylaxis need to be defined to better direct practice in this high-risk population.