BACKGROUND: Treatment of relapsed/refractory acute myeloid or lymphoid leukemia consists of salvage chemotherapy followed by allogeneic hematopoietic stem-cell transplantation. Intravenous fludarabine, cytarabine, and filgrastim is an effective regimen in this setting. In view of the lack of availability of intravenous fludarabine in Mexico from 2009-2013, we substituted an equivalent oral fludarabine dose (40 mg) for the intravenous formulation. OBJECTIVE: This is a retrospective comparison of the toxicity and effectiveness of oral fludarabine, cytarabine, and filgrastim versus intravenous fludarabine, cytarabine and filgrastim. RESULTS: A total of 44 patients with relapsed/refractory acute myeloid leukemia or acute lymphoid leukemia treated in an academic medical center from 2005-2013 with oral fludarabine, cytarabine and filgrastim (21 patients) or intravenous fludarabine, cytarabine and filgrastim (23 patients) were included in the analysis. There was a trend towards a higher complete remission rate and a longer overall survival following intravenous fludarabine, cytarabine, and filgrastim as compared with oral fludarabine, cytarabine, and filgrastim: complete remission rates 39.1 vs. 23.8% (p = 0.342) and overall survival 6.14 vs. 10.78 months (p = 0.363), respectively. A higher incidence of neutropenic fever (100 vs. 76.2%; p = 0.019) and septic shock (34.8 vs. 0%; p = 0.003) and a longer hospitalization (26.8 vs. 19.4 days; p = 0.046) were observed with intravenous fludarabine, cytarabine, and filgrastim. In multivariate analysis, factors associated with a shorter survival were septic shock (HR: 3.93; 95% CI: 1.67-9.25; p = 0.002) and a higher number of previous treatments (HR: 2.5; 95% CI: 1.26-4.99; p = 0.009). Complete remission was associated with better survival (HR: 0.18; 95% CI: 0.08-0.44; p < 0.001). CONCLUSIONS: Further studies are needed to determine the optimal dose and timing of oral fludarabine when given as part of the fludarabine, cytarabine, and filgrastim regimen for relapsed/refractory acute leukemia. Our data suggest that the dose of oral fludarabine used, 40 mg/m² per day for five days, may be a lower bioequivalent dose to the intravenous dose in fludarabine, cytarabine, and filgrastim.