Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging, and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial. Using low-coverage whole-genome sequencing, tumor-associated copy-number variations in CSF-derived cfDNA are investigated as an MRD surrogate. MRD is detected at baseline in 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients declines with therapy, yet those with persistent MRD have significantly higher risk of progression. Importantly, MRD detection precedes radiographic progression in half who relapse. Our findings advocate for the prospective assessment of CSF-derived liquid biopsies in future trials for medulloblastoma. [Display omitted] • Biomarkers for response monitoring are lacking in medulloblastoma • CSF-derived cfDNA profiling captures chromosomal landscapes of primary tumors • Detectability of CNVs in cfDNA carries clinical utility as an MRD biomarker • Liquid biopsy analyses should be incorporated into future medulloblastoma trials Liu et al. describe the utility of profiling CSF-derived cfDNA from 123 children with medulloblastoma. Use of low-coverage whole-genome sequencing captures tumor-associated CNVs as MRD surrogate, allowing correlation with tumor burden and prediction of disease progression. Serial analysis of cfDNA reflects evolution of the medulloblastoma genome in response to therapy. [ABSTRACT FROM AUTHOR]