Assay of cell-free DNA in blood offers an approach to assessment of tumor DNA. We sought to determine whether Epstein-Barr virus (EBV) DNA in cell-free blood is also a good surrogate for the presence of tumor DNA in children with Hodgkin lymphoma, as it is in adults, and whether it correlates with pediatric outcomes. Pediatric patients enrolled in a Children's Oncology Group trial (AHOD0031) were studied at baseline and at 8 days after the initiation of treatment. At baseline, EBV DNA in cell-free blood correlated with the presence of EBV in tumor, and EBV DNA 8 days after the initiation of therapy predicted inferior event-free survival. EBV DNA in cell-free blood warrants further investigation as a marker of inadequate tumor response in Hodgkin lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00025259.