The Southwest Oncology Group undertook a phase II study of teniposide (VM-26) and ifosfamide in refractory adult acute lymphocytic leukemia. The 49 evaluable patients were heavily pretreated; 15 of these had received only one prior induction attempt. Two treatment regimens were used. Eighteen patients received VM-26 (30 mg/m2) on Days 1-5 and ifosfamide (1000 mg/m2) by continuous iv infusion on Days 1-5. When acceptable toxicity was observed, the dose of VM-26 was increased and 30 patients received VM-26 (50 mg/m2) on Days 1-5 in addition to ifosfamide. Complete remission (CR) was observed in two patients who received the lower-dose VM-26 regimen and in six patients who received the higher-dose regimen. Of the eight patients who achieved CR, six were found among the 15 patients who had received only one prior induction therapy. Hematologic toxicity was the major toxic effect observed, with 41 patients (84%) having wbc counts less than 1000/microliter during induction therapy. Nonhematologic toxicity was dose-limiting in seven patients for the following reasons: hematuria (four patients), neurological disturbance (one), and mucositis (two). The combination of VM-26 and ifosfamide is capable of producing CR in refractory acute lymphocytic leukemia in adults with manageable toxicity. Inclusion of the combination in a multidrug consolidation regimen for newly diagnosed patients is an appropriate avenue for further study.