OSI-211 (liposomal lurtotecan), was evaluated using several different dose schedules (1 mg/kg, d1–5, 1.75 mg/kg d1, 3, 5 and 6 mg/kg d1, 8) in severe combined immunodeficient (SCID) mouse models of acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) with early treatment (ET, days 6–8) or late treatment (LT, days 15–19), examining early and advanced disease, respectively. Due to the aggressive nature of the Molt-4 model, the ET and LT were accelerated to day 3 or 4 and day 8 post-implant, respectively. For each model, 2×10 7 (KBM-3B) or 1×10 7 (Molt-4, HL-60 and CEM) leukemia cells were injected intravenously into the tail vein. Each control and test group consisted of eight animals. All three schedules (1 mg/kg qd1–5, 1.75 mg/kg d1, 3, 5 and 6 mg/kg d1, 8) increased the life span of OSI-211 treated animals in each model, with a tendency toward improved efficacy with the 6 mg/kg d1, 8 schedule. As a result, the activity of the 6 mg/kg d1, 8 schedule is detailed for each model. ET significantly ( P<0.005) increased survival in the KBM-3B model with 86% long-term survivors (LTS). Using PRC analysis, human β-globin gene sequences in one or several tissues were amplified in all but 3 LTS, suggesting minimal residual disease in 26 of the 29 LTS. LT also significantly ( P<0.005) improved average life span in the KBM-3B model, with an average ILS=196±11% and one LTS. Treatment of HL-60 leukemia animals significantly ( P<0.005) increased life span, with an ILS=213±9% and two LTS for ET, and with an ILS=219±4% and no LTS for LT. Treatment of Molt-4 animals, the most aggressive leukemia model tested, significantly ( P<0.005) increased life span, with an average ILS=181±3% and no LTS for ET and an average ILS=172±1% with no LTS for LT. In the CEM model, ET resulted in a significantly ( P<0.005) improved ILS=244±24% with one LTS. In comparison to OSI-211, treatment with DaunoXome, the liposomal formulation of daunorubicin, a drug with clinical efficacy in AML and ALL, had no effect on survival in the KBM-3B, nor Molt-4 A4 leukemia models when administered at its maximum or near maximum tolerated doses of 3 mg/kg d1, 8. These data demonstrate that OSI-211 has potent antileukemia activity in preclinical SCID mouse AML and ALL leukemia models, supporting the clinical investigation of OSI-211 for hematological malignancies.