With the use of risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the past 40 years. However, a substantial portion of patients, many of whom have no known risk factors, experience relapse. Taking a genome-wide approach, in the present study, we evaluated the relationships between genotypes at 444 044 single nucleotide polymorphisms (SNPs) with the risk of relapse in 2535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We identified 134 SNPs that were reproducibly associated with ALL relapse. Of 134 relapse SNPs, 133 remained prognostic after adjusting for all known relapse risk factors, including minimal residual disease, and 111 were significant even among patients who were negative for minimal residual disease after remission induction therapy. The C allele at rs7142143 in the PYGL gene was associated with 3.6-fold higher risk of relapse than the T allele (P = 6.7 × 10(-9)). Fourteen of the 134 relapse SNPs, including variants in PDE4B and ABCB1, were also associated with antileukemic drug pharmacokinetics and/or pharmacodynamics. In the present study, we systematically identified host genetic variations related to treatment outcome of childhood ALL, most of which were prognostic independent of known risk factors for relapse, and some of which also influenced outcome by affecting host dis-position of antileukemic drugs. All trials are registered at www.clinicaltrials.gov or www.cancer.gov (COG P9904: NCT00005585; COG P9905: NCT00005596; COG P9906: NCT00005603; St Jude Total XIIIB: NCI-T93-0101D; and St Jude Total XV: NCT00137111).