Leukemic cells from a significant number of children with acute lymphoblastic leukemia (ALL) express protein antigens characteristic of both lymphoid and myeloid cells, yet the clinical significance of this immunophenotype has remained controversial. In the current study, we have determined relationships between myeloid antigen expression and treatment outcome in a large cohort of children with newly diagnosed ALL. A total of 1,557 children enrolled on risk-adjusted Children's Cancer Group studies were classified as myeloid antigen positive (My+) or myeloid antigen negative (My-) B-lineage ALL (BL) or T-lineage ALL (TL), according to expression of CD7, CD19, CD13, and CD33 antigens on the surface of their leukemic cells. My+ patients in both BL and TL groups were more likely than My- patients to have favorable presenting features. Induction therapy outcome was similar for My+ and My- patients in both the BL and TL categories. Importantly, 4-year event-free survival (EFS) was similar for My+ BL (77.0%, standard deviation [SD] = 4.0%) versus My- BL (75.9%, SD = 1.8%) and for My+ TL (72.7%, SD = 7.1%) versus My- TL (70.1%, SD = 5.7%). An overall relative hazard rate (RHR) of 0.89 (P = .49) was determined by a cross strata analysis for My+ versus My- patients. Moreover, similar EFS and RHR also were found when My+ and My- BL patients were compared according to National Cancer Institute risk classification. Thus, patients with My+ ALL have similar treatment outcomes as My- ALL patients. In contrast to previous studies, this result was independent of treatment risk category, demonstrating that myeloid antigen expression was not an adverse prognostic factor for childhood ALL.