Anticoagulant treatment of pediatric cancer-associated venous thromboembolism (VTE) has not been prospectively evaluated. Management of anticoagulation for cancer-associated VTE is often challenged by drug interactions and treatment interruptions. A total of 56 (11.2%) of the 500 children with VTE who participated in the recent EINSTEIN-Jr randomized study had cancer (hematologic malignancy (n=36 [64.3%]) or a solid malignant tumor (n=20 [35.7%]). Children were allocated to either therapeutic-dose bodyweight-adjusted oral rivaroxaban (n=40) or standard anticoagulation with heparins with or without vitamin K antagonists (n=16) and received a median of 30 concomitant medications. Based on sparse blood sampling at steady-state, rivaroxaban PK parameters were derived using population PK modeling. During 3 months of treatment, no recurrent VTE or major bleeding occurred (95% confidence interval, 0.0-6.4%) and repeat imaging at 3 months showed complete or partial vein recanalisation in 20 (38.5%) and 24 (46.2%) of 52 evaluable children. Anticoagulant treatment was interrupted 70 times in 26 (46.4%) children because of thrombocytopenia, invasive procedures or adverse events, for a mean individual period of 5.8 days. Anticoagulant therapy was resumed in therapeutic doses and was not associated with thrombotic or bleeding complications. Rivaroxaban exposures were within the adult exposure range and similar to those observed in children with VTE who did not have cancer-associated VTE. Anticoagulation with either rivaroxaban or heparins with or without vitamin K antagonists appeared safe and efficacious and was associated with reduced clot burden in most children with cancer-associated VTE, including those who had anticoagulant treatment interruptions. Rivaroxaban exposures were within the adult exposure range despite significant polypharmacy use. The study is registered to www.clinicaltrials.gov as NCT02234843.