To evaluate the efficacy and toxicity profiles of a combination regimen of homoharringtonine (HHT) and low-dose cytarabine (ara-C) in patients with Philadelphia chromosome (Ph)–positive chronic myelogenous leukemia (CML) who had experienced treatment failure with interferon alfa (IFN) therapy. One hundred five patients were treated: 100 in chronic phase (15 with cytogenetic clonal evolution) and five in accelerated phase. Their median age was 52 years; all had been treated unsuccessfully with IFN; 94% were in late chronic phase; 43% had been exposed to ara-C and 11% had been exposed to HHT. Patients received HHT 2.5 mg/m2 by continuous infusion daily for 5 days and ara-C 15 mg/m2 daily in two subcutaneous injections for 5 days every 4 weeks. The outcome of the 100 patients in chronic phase was compared with a previous study group of 73 patients treated with HHT alone. Overall, the complete hematologic response (CHR) rate in chronic phase was 72%; the cytogenetic response rate was 32%(major response, 15%; complete response, 5%). Toxicities were acceptable, mostly related to moderate diarrhea (3%), headaches (3%), cardiovascular events (3%), and myelosuppression-associated complications (3% to 14%). With a median follow-up period of 25 months, the estimated 4-year survival rate was 55%. Response rates were identical with HHT plus ara-C versus HHT alone, but the survival was significantly longer with the combination after accounting for differences in the study groups and by multivariate analysis. The combination regimen of HHT and ara-C is effective and safe in patients with CML who have experienced treatment failure with IFN and needs to be investigated together with IFN as part of front-line CML therapy. The addition of ara-C did not improve the response rates but may have improved survival, perhaps through suppression of clones related to disease transformation.