Objectives: CPX-351 (Vyxeos®; daunorubicin [D] and cytarabine [C] liposome for injection for intravenous use) is approved by the US FDA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Primary analysis of the pivotal phase 3 study (NCT01696084) that formed the basis for approval evaluated patients (pts) 60–75 y with newly diagnosed high-risk/secondary AML; after 20.7 mo median follow-up, induction then consolidation with CPX-351 significantly improved median overall survival (OS) vs conventional 7+3, with a comparable safety profile. We now report the prospectively planned, final 5-y follow-up results, including outcomes by age. Materials and Methods: Pts were randomized 1:1 to receive 1–2 induction cycles of CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] as a 90-minute infusion on Days 1, 3, & 5 [2nd induction: Days 1 & 3]) or 7+3 (C 100 mg/m2/d continuously for 7 d + D 60 mg/m2 on Days 1–3 [2nd induction: 5+2]). Pts achieving complete remission (CR) or CR with incomplete platelet/neutrophil recovery (CRi) could receive up to 2 consolidation cycles. Pts received hematopoietic cell transplantation (HCT) at the physician's discretion. Pts were followed until death or up to 5 y after randomization. Results: 309 pts were randomized to CPX-351 (n = 153) or 7+3 (n = 156). The Kaplan-Meier (KM)–estimated survival rates were higher for CPX-351 vs 7+3 at 3 y (21% vs 9%) and 5 y (18% vs 8%). Among pts who died, the most common primary cause of death was progressive leukemia (CPX-351: 56%; 7+3: 53%). After a reverse KM-estimated median follow-up of 60.65 mo, improved median OS with CPX-351 vs 7+3 was maintained (9.33 vs 5.95 mo; HR = 0.70 [95% CI: 0.55, 0.91]), with an HR that was very stable and consistent with the primary analysis. Improved median OS with CPX-351 vs 7+3 was also maintained in pts 60–69 y (9.59 vs 6.87 mo; HR = 0.73 [95% CI: 0.54, 0.99]) and 70–75 y (8.87 vs 5.62 mo; HR = 0.52 [95% CI: 0.34, 0.77]). Among pts who underwent HCT (CPX-351: 35%; 7+3: 25%), the KM-estimated survival rate landmarked from the HCT date was higher for CPX-351 vs 7+3 at 3 y (56% vs 23%), and median OS landmarked from the HCT date was not reached for CPX-351 vs 10.25 mo for 7+3 (HR = 0.51 [95% CI: 0.28, 0.90]). Among pts who achieved CR+CRi (CPX-351: 48%; 7+3: 33%), the KM-estimated survival rate was higher for CPX-351 vs 7+3 at 3 y (36% vs 23%) and at 5 y (30% vs 19%), and median OS was longer with CPX-351 vs 7+3 (21.72 vs 10.41 mo; HR = 0.59 [95% CI: 0.39, 0.88]). Further, 41/73 (56%) pts in the CPX-351 arm and 24/52 (46%) in the 7+3 arm who achieved CR+CRi proceeded to HCT; in these pts, median OS landmarked from the HCT date was not reached for CPX-351 vs 11.65 mo for 7+3 (HR = 0.50 [95% CI: 0.26, 0.97]). Discussion: After 5 y of follow-up, improved OS with CPX-351 vs conventional 7+3 chemotherapy was maintained in this phase 3 study, overall and regardless of pt age, in pts who underwent HCT, and among pts who achieved CR+CRi. The longer OS for CPX-351 vs 7+3 in pts who had HCT and those who achieved CR+CRi suggests potentially deeper responses may be achieved with CPX-351. Conclusion: These data support prior evidence that CPX-351 can produce or contribute to long-term remission and survival in older pts with newly diagnosed high-risk/secondary AML.