Leukemic cells from a subset of children with acute lymphoblastic leukemia (ALL) express lymphoid antigens of both T lineage and B lineage, but the clinical significance of this immunophenotype is unknown. We now report the first comprehensive comparison of treatment outcomes among a large cohort of children with CD2+ CD19+ biphenotypic ALL (N = 77), B-lineage ALL (BL) (N = 1,631), or T-lineage ALL (TL) (N = 347) ALL who were treated on risk-adjusted Children's Cancer Group (CCG) protocols. CD2+ CD19+ patients were more similar to BL than TL patients with respect to presenting features and antigen expression. The percentages of patients achieving successful induction therapy outcome were 98.7%, 97.8%, and 97.3% for CD2+ CD19+, BL, and TL patients, respectively. Univariate comparisons of 4-year event-free survival (83.7%, 72.8%, 75.2% for CD2+ CD19+, BL, and TL patients, respectively) achieved borderline significance (CD2+ CD19+ B, P = .08; CD2+ CD19+ v T, P = .07). Relative hazard rate (RHR) estimates for BL and TL compared with CD2+ CD19+ were 1.79 and 1.90, respectively, implying a better outcome for biphenotypic patients. However, multivariate adjusted RHRs for BL and TL compared with CD2+ CD19+ were 1.43 (P = .29) and 1.16 (P = .76), respectively, suggesting a significant reduction in risk for BL or TL patients once adjustment was made for the more favorable characteristics of the CD2+ CD19+ group. Thus, pediatric ALL patients treated on contemporary CCG protocols who present with CD2+ CD19+ biphenotypic leukemia generally have good treatment outcomes, due in part to their favorable presenting features.