Among the strongest associations with pediatric B-cell acute lymphoblastic leukemia (B-ALL) are risk non-coding variants localized in the intron of ARID5B (AT-rich interaction domain 5B), a poorly characterized DNA-binding protein. In this study, we defined the interactome of ARID5B by LC-MS/MS and identified transcriptional repressors HDAC1, HDAC2, MIER1 and C16ORF87 as interactors. Structural predictions revealed that ARID5B and its interactors assemble into a repressor complex. We further validated and characterized the molecular function of the ARID5B repressor complex in B cells.