The importance of preventing venous thromboembolism (VTE) in hospitalized adults is well recognized. We recently developed and published our institutional guidelines for the prevention of VTE in high-risk hospitalized patients in a pediatric hospital. The objective of this prospective observational study was to evaluate the safety of anticoagulation after these guidelines were instituted. The primary outcome was major bleeding and secondary outcomes included minor bleeding and VTE. Eighty-nine patients were enrolled, with a mean age of 16.6 years. The most common risk factors for VTE were impaired mobility, lower extremity orthopedic surgery, and obesity. The majority of patients (63%) had 3 or more risk factors. There were 2 major bleeding events, and minor bleeding occurred in 5 patients, all in patients who had undergone major orthopedic surgery. Therefore the risk of major bleeding in orthopedic surgery patients was 4% (2/51), and 0% (0/38) in the remaining patients. No patient developed a non–catheter-related VTE, which was the primary intent of our guidelines. Although there remains much work to be done to optimize VTE strategies in pediatric patients, this study provides information regarding the risks of VTE prophylaxis using a pragmatic approach in hospitalized patients with multiple risk factors for VTE. More studies are needed to better define the risk:benefit ratio in this population.