Childhood acute lymphoblastic leukemia survival approaches 90%. New strategies are needed to identify the 10-15% that evade cure. We applied targeted, sequencing-based genotyping of 25 000 to 34 000 preselected potentially clinically relevant single nucleotide polymorphisms (SNPs) to identify host genome profiles associated with relapse risk in 352 patients from the Nordic ALL92/2000 protocols and 426 patients from the German BFM ALL2000 protocol. Patients were enrolled 1992 2008 (median follow-up: 7·6 years). Eleven cross-validated SNPs were significantly associated with risk of relapse across protocols. SNP and biological pathway level analyses associated relapse risk with leukemia aggressiveness, glucocorticosteroid pharmacology/response and drug transport/metabolism pathways. Classification and regression tree analysis identified three distinct risk groups defined by end of induction residual leukemia, white blood cell count, and variants in myeloperoxidase (MPO), estrogen receptor 1 (ESR1), lamin B1 (LMNB1), and matrix metalloproteinase-7 (MMP7) genes, ABC transporters, and glucocorticosteroid transcription regulation pathways. Relapse rates ranged from 4% (95% CI: 1·6-6·3%) for the best (72% of patients) to 76% (95% CI: 41-90%) for the worst group (5% of patients, P<0·001). Validation of these findings and similar approaches to identify SNPs associated with toxicities may allow future individualized relapse and toxicity risk-based treatments adaptation.Leukemia accepted article preview online, 03 July 2014; doi:10.1038/leu.2014.205.