MHC Class II antigen processing and presentation to CD4+ T cells is important in anti-tumor immunity. ETV6-AML1-positive precursor-B acute lymphoblastic leukemia (pre-B ALL) is associated with good outcome and late relapse. We analyzed HLA-DR and the MHC Class II processing components HLA-DO, HLA-DM, and Class II-associated invariant chain peptide (CLIP) expression, in ETV6-AML1-positive and ETV6-AML1-negative ALL. Overall, CLIP expression was low, while HLA-DM was significantly higher in ETV6-AML1-positive cells. No significant difference in HLA-DO was observed. The HLA-DR(high)/CLIP(low)/HLA-DM(high) phenotype strongly suggests that ETV6-AML1 leukemia will induce favorable immune responses and may in part explain the characteristic late relapses associated with ETV6-AML1 pre-B ALL.