Liposomal daunorubicin and cytarabine (CPX-351) improved overall survival (OS) compared with 7+3 chemotherapy in older patients with secondary acute myeloid leukemia (AML); to date, there have been no randomized studies in younger patients. The high-risk cohort of the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adults with newly diagnosed adverse cytogenetic AML or high-risk myelodysplastic syndromes (MDS). A total of 189 patients were randomized (median age, 56 years). Per clinical criteria, 49% of patients had de novo AML, 20% had secondary AML, and 30% had high-risk MDS. MDS-related cytogenetics were present in 73% of the patients, with a complex karyotype in 49%. TP53 was the most common mutated gene, in 43%. Myelodysplasia-related gene mutations were present in 75 (44%) patients. The overall response rate (CR + CRi) after course 2 was 64% and 76% for CPX-351 and FLAG-Ida, respectively. There was no difference in OS (13.3 months vs 11.4 months) or event-free survival in multivariable analysis. However, relapse-free survival was significantly longer with CPX-351 (median 22.1 vs 8.35 months). There was no difference between the treatment arms in patients with clinically defined secondary AML or those with MDS-related cytogenetic abnormalities; however, an exploratory subgroup of patients with MDS-related gene mutations had significantly longer OS with CPX-351 (median 38.4 vs 16.3 months). In conclusion, the OS of younger patients with adverse risk AML/MDS was not significantly different between CPX-351 and FLAG-Ida.