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Survival of patients ≥40 years of age with Philadelphia-negative acute lymphoblastic leukemia (ALL) remains poor with current therapeutic approaches. It is unknown whether allogeneic hematopoietic stem-cell transplantation (HSCT) in first remission confers a survival benefit compared to a chemotherapy-only approach. We retrospectively compared the outcome of patients >40 years treated with HSCT or chemotherapy alone in first remission (n = 40 in each cohort). Three-year overall survival (OS) and disease-free survival (DFS) were not significantly different between the chemotherapy-only and HSCT groups (OS, 46% [31–68] vs. 40% [27–59], P = 0.35; DFS, 31% [18–52] vs. 40% [27–59], P = 0.98). The 3-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 61% [41–76] and 9% [2–21] for the chemotherapy-only group and 28% [15–43] and 32% [17–47] for the transplant group (CIR, P = 0.011; NRM, P = 0.014). Allogeneic transplantation for patients ≥40 years with Ph-negative ALL in first remission is associated with a lower CIR, but this benefit is offset by considerable NRM as compared with chemotherapy-only approach. HSCT may be beneficial in patients with high-risk disease features. Am. J. Hematol. 91:793–799, 2016. © 2016 Wiley Periodicals, Inc.