The causes of individual relapses in children with acute lymphoblastic leukemia (ALL) remain incompletely understood. We evaluated the contribution of germline genetic factors to relapse in 2225 children treated on Children's Oncology Group trial AALL0232. We identified 302 germline single-nucleotide polymorphisms (SNPs) associated with relapse after adjusting for treatment and ancestry and 715 additional SNPs associated with relapse in an ancestry-specific manner. We tested for replication of these relapse-associated SNPs in external data sets of antileukemic drug pharmacokinetics and pharmacodynamics and an independent clinical cohort. 224 SNPs were associated with rapid drug clearance or drug resistance, and 32 were replicated in the independent cohort. The adverse risk associated with black and Hispanic ancestries was attenuated by addition of the 4 SNPs most strongly associated with relapse in these populations (for blacks: model without SNPs hazard ratio (HR) = 2.32, P = 2.27 × 10-4, model with SNPs HR = 1.07, P = 0.79; for Hispanics: model without SNPs HR = 1.7, P = 8.23 × 10-5, model with SNPs HR = 1.31, P = 0.065). Relapse SNPs associated with asparaginase resistance or allergy were overrepresented among SNPs associated with relapse in the more asparaginase intensive treatment arm (20/54 in Capizzi-methorexate arm vs 8/54 in high-dose methotrexate arm, P = 0.015). Inherited genetic variation contributes to race-specific and treatment-specific relapse risk.