Venous thromboembolism (VTE), composed mainly of deep venous thrombosis (DVT) and pulmonary embolism, is a top contributor to harm in hospitalized children. Critically ill adolescents are at high risk of VTE. Studies indicate that in addition to hypercoagulability, endothelial injury and venous stasis from central venous catheters are key determinants of DVT in critically ill adolescents. The appropriate strategy to prevent VTE in these adolescents is unknown. This results in wide variation in practice, low use of thromboprophylaxis, and increasing incidence of VTE in adolescents. Due to lack of pediatric-specific evidence, thromboprophylaxis practice in critically ill adolescents is extrapolated from adults. Pediatric patient safety initiatives recommend mechanical thromboprophylaxis (mTP) for these adolescents to account for the unique differences in the epidemiology of VTE in adolescents. Given the efficacy of pharmacological thromboprophylaxis (pTP) in adults, the pediatric initiatives recommend strongly considering combined mTP and pTP (mTP+pTP), which likely attenuates venous stasis from a central venous catheter and hypercoagulability. Yet, between mTP+pTP and mTP alone, the American Society of Hematology in 2018 has suggested using mTP alone for medical inpatients because of uncertainty in the net clinical benefit of mTP+pTP with harm likely outweighing benefits. With the support of the PALISI Network, the Adjunctive THromboprophylaxis with Enoxaparin in iNtubated Adolescents (ATHENA) Trial will test the central hypothesis is that mTP+pTP safely reduces the risk of VTE in critically ill adolescents over mTP alone. It will provide much needed pediatric-specific evidence that will inform clinical practice. It will also enhance our understanding of the pathophysiology of VTE in critically ill adolescents.