Summary Background Homoharringtonine-based induction regimens have been widely used in China for patients with acute myeloid leukaemia. However, their efficacy has not been tested in a multicentre randomised controlled trial in a large population. We assessed the efficacy and safety of homoharringtonine-based induction treatment for management of newly diagnosed acute myeloid leukaemia. Methods This open-label, randomised, controlled, phase 3 study was done in 17 institutions in China between September, 2007, and July, 2011. Untreated patients aged 14–59 years with acute myeloid leukaemia were randomly assigned (by a computer-generated allocation schedule without stratification) to receive one of three induction regimens in a 1:1:1 ratio: homoharringtonine 2 mg/m2 per day on days 1–7, cytarabine 100 mg/m2 per day on days 1–7, and aclarubicin 20 mg/day on days 1–7 (HAA); homoharringtonine 2 mg/m2 per day on days 1–7, cytarabine 100 mg/m2 per day on days 1–7, and daunorubicin 40 mg/m2 per day on days 1–3 (HAD); or daunorubicin 40–45 mg/m2 per day on days 1–3 and cytarabine 100 mg/m2 per day on days 1–7 (DA). Patients in complete remission were offered two cycles of intermediate-dose cytarabine (2 g/m2 every 12 h on days 1–3). The primary endpoints were the proportion of patients who achieved complete remission after two cycles of induction treatment and event-free survival in the intention-to-treat population. The trial is registered in the Chinese Clinical Trial Register, number ChiCTR-TRC-06000054. Findings We enrolled 620 patients, of whom 609 were included in the intention-to-treat analysis. 150 of 206 patients (73%) in the HAA group achieved complete remission versus 125 of 205 (61%) in the DA group (p=0·0108); 3-year event-free survival was 35·4% (95% CI 28·6–42·2) versus 23·1% (95% CI 17·4–29·3; p=0·0023). 133 of 198 patients (67%) in the HAD group had complete remission ( vs DA, p=0·20) and 3-year event-free survival was 32·7% (95% CI 26·1–39·5; vs DA, p=0·08). Adverse events were much the same in all groups, except that more patients in the HAA (12 of 206 5·8%) and HAD (13 of 198 6·6%) groups died within 30 days than in the DA group (two of 205 1%; p=0·0067 vs HAA; p=0·0030 vs HAD). Interpretation A regimen of homoharringtonine, cytarabine, and aclarubicin is a treatment option for young, newly diagnosed patients with acute myeloid leukaemia. Funding Chinese National High Tech Programme, Key Special Research Foundation of the Ministry of Science and Technology of China, National Nature Science Foundation of China, National Clinical Key Specialty Construction Project.