Lintuzumab-Ac255 is a humanized anti-CD33 antibody linked to Actinium-225 delivering high-energy alpha-particles to leukemia cells, inciting double-strand DNA breaks and cell death. This phase 1 study assessed the safety and efficacy of lintuzumab-Ac225 after CLAG-M salvage therapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Primary objectives were determination of maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and safety. Using a 3 + 3 dose-escalation design, 21 patients were enrolled sequentially into 4 cohorts to receive a lintuzumab-Ac225 infusion (0.25-1.0 µCi/kg) 7 ( + 2) days after CLAG-M (days 1-6); 5 additional patients received the RP2D. Of evaluable patients, 86.7% had high-risk disease. The MTD and RP2D was 0.75 µCi/kg. Common grade 3/4 adverse events were febrile neutropenia (65.4%) and decreased white blood cells (50%). The composite complete remission (CRc) rates (CR/CRi) were 56.6% overall, 50% in patients with mutated TP53, and 38.5% in prior venetoclax-treated patients. Measurable residual disease (MRD)-negativity was achieved in 8 of 12 responders. Among all patients (n = 26), estimated 2-year OS was 23.1% (95% CI, 9.4-40.3) and estimated 1-year PFS was 30.8% (95% CI, 14.6-48.5). Lintuzumab-Ac225 plus CLAG-M was well tolerated with expected, manageable toxicities, while yielding deep and meaningful responses in high-risk R/R AML patients.