Children with malignant mediastinal masses have increased thrombotic events (TE). We examined primary thromboprophylaxis in reducing TE. Eligible subjects were started on enoxaparin thromboprophylaxis and compared to a cohort without. There were 15 TEs among 76 subjects for an incidence of 19.7%. Mediastinal compression directly led to TE, (M-TE) in 9.2% of subjects requiring 2-fold longer duration of therapeutic anticoagulation. Primary thromboprophylaxis revealed a trend towards reduction in M-TE although not statistically significant. The M-TE subjects had greater superior vena caval compression at diagnosis (p=0.033). We conclude that strategic thromboprophylaxis guided by monitoring dynamic vascular compression can improve TE outcomes.