Background Patients with relapsed or refractory acute myeloid leukaemia have a poor prognosis. Outcomes with conventional intensive salvage chemotherapy are suboptimal. We aimed to evaluate the safety and activity of high-dose cytarabine and mitoxantrone in combination with venetoclax in patients with relapsed or refractory acute myeloid leukaemia. Methods This study was a multicentre, open-label, single-arm, phase 1/2 trial. Patients aged 18–75 years, medically fit for intensive chemotherapy (ie, Eastern Cooperative Oncology Group performance status ≤2, adequate hepatic and renal function) with relapsed (haematological relapse from first or second complete remission) or refractory acute myeloid leukaemia (no response after one or two courses of standard induction chemotherapy) were eligible. Patients received venetoclax 400 mg orally once a day on days 1–14 (initial 3-day dose ramp-up), mitoxantrone 10 mg/m² intravenously once a day on days 5–7, and cytarabine (dose level 1, 200 mg/m² continuous intravenous infusion on days 4–10; dose level 2, cytarabine 500 mg/m² intravenously twice a day on days 3–5; or dose level 3, cytarabine 1000 mg/m² intravenously twice a day on days 3–5). Phase 1 applied a 3 + 3 dose-escalation design to determine the primary endpoint of maximum tolerated dose and recommended phase 2 dose. The primary endpoint of phase 2 was the composite complete remission rate by intention-to-treat. Safety was assessed in all patients exposed to venetoclax. The trial is registered with EUDRA-CT, 2018–003025–28, and ClinicalTrials.gov , NCT04330820 , and is completed. Findings From April 6, 2020, to Aug 31, 2023, 55 patients were enrolled (12 in phase 1 and 43 in phase 2). Median follow-up was 30·8 months (IQR, 26·6–34·1). Median age was 57 years (IQR, 49·0–66·5). 30 (55%) of 55 patients were male and 25 (45%) were female. 25 (45%) of 55 patients had adverse-risk acute myeloid leukaemia according to the European LeukemiaNet 2022 classification and 19 (35%) had previous allogeneic haematopoietic cell transplantation (HCT). The maximum tolerated dose was not reached, and dose level 3 was considered safe and defined as the recommended phase 2 dose. The composite complete remission rate was 75% (95% CI 61–85, 41 of 55 patients). The most common all-grade adverse events were febrile neutropenia (29 [53%] of 55 patients), pneumonia (12 [22%]), and sepsis (12 [22%]). 15 serious adverse events occurred in 14 (13%) patients, of which sepsis and pneumonia were the most common. Potential treatment-related deaths were reported in four patients (sepsis n=3, pneumonia n=1). Interpretation High-dose cytarabine and mitoxantrone plus venetoclax appeared to be safe, showed promising activity, and could be a new therapeutical approach for medically fit patients with relapsed or refractory acute myeloid leukaemia, especially as a bridge to allogeneic HCT. Funding AbbVie.