Background: CPX-351 encapsulates cytarabine (CYT) and daunorubicin (DNR) at a 5:1 molar ratio within liposomes, enabling preferential drug uptake within leukemic blasts and intracellular release, potentially enhancing efficacy in AML. A pair of randomized Phase IIb studies in newly diagnosed older patients (pts) and younger 1st relapse AML pts reported improved rates of morphologic leukemia-free state, CR + CRi, and significant improvements in survival among previously untreated high risk (secondary) pts and among poor-risk 1^st relapse pts. This report presents the results of the multivariate analyses performed on all pts treated in both studies. Methods: Patients 60-75 yo with newly diagnosed AML and ≤ 65 yo with 1^st relapse AML and ECOG PS= 0-2, S_CR < 2.0 mg/dL, total bilirubin < 2.0 mg/dL, ALT/AST <3x ULN, and LVEF ≥ 50% were eligible. Pts with APL, DNR exposure >368 mg/m², active CNS leukemia, and uncontrolled infections were excluded. Pts were randomized 2:1 to receive up to 2 inductions and 2 consolidations with CPX-351 (100 u/m²; D 1, 3, 5) or CYT + DNR (7+3) for newly diagnosed pts or investigator’s choice of salvage chemotherapy for relapsed pts. Allogeneic transplantation was permitted. Univariate and multivariate Cox and logistic regression were used to assess associations between baseline characteristics and overall (OS) and event-free survival (EFS) and 60-day mortality for all pts. The multivariate employed stepwise selection to identify statistically significant prognostic factors after accounting for potential treatment effects. Results: Patient characteristics including cytogenetics were well balanced. Significant negative prognostic factors affecting OS, EFS, and 60-day mortality included relapsed disease (Study 205 participation, HR=2.13, p<0.001), adverse cytogenetics (HR=1.52, p=0.024), and low (<3g/dL) serum albumin (HR=1.82, p=0.005). CPX-351 treatment was a significant positive factor in EFS (HR=0.62, p=0.006). Conclusions: This analysis identified and quantitated disease specific (adverse cytogenetics) and patient specific (albumin<3gm/dL) factors that can be used to better design future studies. Clinical trial information: NCT00788892 and NCT00822094.