We compared outcomes of adult patients with secondary acute myeloid leukemia (sAML) versus de novo AML after non-T-depleted haploidentical stem cell transplant (HaploSCT) with post-transplant cyclophosphamide (PTCy). Seventeen hundred and eleven AML patients (sAML-231, de novo-1480) in first complete remission transplanted from 2010 to 2021, were included. Patients with de novo AML were younger, median age 55.8 versus 60.8 years,p< 0.0001, had better transplantation comorbidity index (HCT-CI) ≥ 3 21.3% versus 40.8%,p< 0.0001 and Karnofsky performance status (KPS) with KPS ≥ 90 in 78% versus 68.5%, respectively,p= 0.002. The two patient groups did not differ with respect to gender, cytomegalovirus serostatus, and cell source. Median time from diagnosis to HaploSCT was 5.2 versus 4.9 months, respectively,p= 0.005. Fewer sAML patients received myeloablative conditioning 35.1% versus 50.1%,p< 0.0001. Two hundred and eleven sAML and 410 de novo AML patients were included in the matched-pair analysis matching two de novo AML with each sAML. No significant difference was observed in any transplantation outcome parameter between the sAML versus de novo AML groups. Two-year non-relapse mortality and relapse incidence did not differ with HaploSCT for de novo versus sAML; 21.4% versus 21%, hazard ratio (HR) = 0.98,p= 0.9 and 23.4% versus 20.6%, HR = 0.92,p= 0.67, respectively. Two-year leukemia-free survival, overall survival, and graft-versus-host disease (GVHD)-free, relapse-free survival were also not different between the de novo AML and sAML groups 55.2% versus 58.4%, HR = 0.95,p= 0.67; 61.4% versus 66.4%, HR = 0.91,p= 0.51 and 46.3% versus 48.2%, HR = 0.92,p= 0.48, respectively. Similarly, the incidence of engraftment as well as acute and chronic GVHD was similar between the 2 cohorts. In conclusion, HaploSCT with PTCy may be able to overcome the bad prognosis of sAML as results are not significantly different to those of HaploSCT in de novo AML.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13045-023-01450-4.