Background: R/R AML has a poor prognosis, thus salvage chemotherapy is used as a bridge to HSCT, however the optimal regimen remains unknown. MEC is commonly used as salvage; ~ 66% of patients achieve CR, with median survival 36 weeks (Arcese et al., JCO, 1991). As the Ara-Couplets regimen has a similar CR/CRi (55%; Larson et al., Leukemia & Lymphoma. 2012), we compared efficacy and toxicity of these regimens in a multi-institution retrospective analysis. Methods: We analyzed records of 43 patients (15 from UIC, 28 from IU) treated with MEC (mitoxantrone 8 mg/m², etoposide 80 mg/m² and cytarabine 1 g/m² x 5 days) and 36 patients treated with Ara-C Couplets (mitoxantrone 30 mg/m² daily and cytarabine 2 g/m² twice daily, days 1 and 5) between 1998 and 2017 (n = 79). Results: Baseline characteristics including gender, race, Charlson Comorbidity Index and age were well balanced. Unfavorable cytogenetics were seen in 14 of MEC and 9 of the Couplets patients (p = ns). CR/CRi was achieved in 21 MEC and 20 Couplets patients (p = 0.65), OS was 196 days vs. 240 days respectively (p = 0.46), and PFS 156 days and 117.5 days respectively (p = 0.86). Seventeen MEC (17/43; 39.5%) and Couplets patients (17/36; 47%) went onto HSCT (p = 0.49). Median ANC recovery was 32 (MEC) and 40 days (Couplets; p = 0.37), while median platelet recovery was significantly different, at 36 and 55 days respectively (p = 0.04). Notably, Grade 3/4 GI toxicity occurred in 8 MEC (18.6%) and only one Couplets patient (2.4%; p = 0.03). In the Couplets group, 2/36 patients experienced cardiac toxicity (5.6%; CHF grades 3/4). The most common adverse event was febrile neutropenia (FN; 95% (MEC) and 86% respectively; p = 0.09). Conclusions: This is the first study directly comparing these salvage regimens in R/R AML; and using a racially diverse population of patients. While both are equally effective as a bridge to HSCT, MEC results in significantly more GI toxicities, and a higher incidence of FN, despite faster platelet recovery. Comparative studies in this population are rare, suggesting the need for larger studies to establish the optimal salvage chemotherapy regimen.