Background: In relapsed/refractory AML, current second-line cytoreductive regimens remain relatively ineffective. A combination of mitoxantrone, etoposide and cytarabine (MEC) is commonly used as second-line therapy and confers response rates of 18-28% with a median OS of 25-32 weeks. The benefit of mitoxantrone here is unclear with cardiac toxicity limiting its use in the face of prior anthracycline exposure. In a retrospective study, we looked at the efficacy of a combination of etoposide and cytarabine (EC) as a cytoreductive regimen in this population. Methods: At our center, 32 patients with relapsed/refractory AML received etoposide 100mg/m²/day on days 1-5, and cytarabine 3 g/m² twice daily on days 1-4, either as second- or third-line induction. Post induction bone marrow biopsies were used to determine response. Results: Of 32 patients, 15 were male. The median age was 55.5 years. Karyotypes were unfavorable in 20, intermediate in 9, favorable in 1, unknown in 2 patient(s). First line induction regimens included standard ‘7+3’ with cytarabine and idarubicin/daunorubicin (n=6), high-dose cytarabine with mitoxantrone (n= 25) or sapacitabine on trial (n=1). 20 patients were primary refractory; 12 had relapsed disease with median time to relapse of 8 months. 25 patients (78%) received EC as 2^nd line and 7 (22%) as 3^rd line therapy. 1 patient did not complete his EC course due to overwhelming infection. With EC, 15 patients (47%) achieved remission, 60% of whom received allogeneic stem cell transplant consolidation. 47% of patients in remission relapsed, all within 1 year. At a median follow-up of 14.7 months post EC, median OS was 4.5 months. In univariate analyses, males (p= 0.04) and patients ≥ 60 years of age (p=0.004) had a significantly worse PFS. Unfavorable cytogenetics did not affect PFS or OS. Complications with EC included hand-foot syndrome, neutropenic fever, infections and cytopenias. Conclusions: EC produces superior CRs and comparable OS when compared to MEC for relapsed/refractory AML without the use of a cardiotoxic drug. However, incorporation of novel agents such as clofarabine should be considered to further improve responses and survival.