Genomic alterations of IKZF1 are common and associated with adverse clinical features in B-ALL. The relationship between the type of IKZF1 alteration, disease subtype and outcome are incompletely understood. Leukemia subtype and genomic alterations were determined using transcriptome and genomic sequencing and SNP microarray in 688 pediatric patients with B-ALL in St. Jude Total Therapy 15 and 16 studies. IKZF1 alterations were identified in 115 (16.7%) patients, most commonly in BCR::ABL1 (78%) and CRLF2- rearranged, BCR::ABL1- like B-ALL (70%). These alterations were associated with 5-year cumulative incidence of relapse (CIR) of 14.8 ± 3.3% compared to 5.0 ± 0.9% for patients without any IKZF1 alteration ( P < 0.0001) . IKZF1 deletions of exon 4-7 ( P = 0.0002), genomic IKZF1 plus with any IKZF1 deletion ( P = 0.006) or with focal IKZF1 deletion ( P = 0.0007), and unfavorable genomic subtypes ( P < 0.005) were independently adversely prognostic factors. Associations of genomic IKZF1 plus and exon 4-7 deletions with adverse outcomes were confirmed in an independent cohort. Genomic IKZF1 plus with any IKZF1 deletion, IKZF1 deletion of exon 4-7, and unfavorable subtype confer increased risk of relapse. The type of IKZF1 alteration, together with the subtype, are informative for risk stratification and predict response in patients with B-ALL.