Background: Elderly candidates for hematopoietic stem cell transplantation (HSCT) cannot tolerate myeloablative conditioning regimens because of regimen-related toxicity and mortality rates. To lower them in elderly patients with acute myeloid leukemia (AML) who underwent 1-haplotype mismatched (haploidentical) HSCT, we designed a conditioning regimen with total marrow/total lymphoid irradiation (TMI/TLI) and low chemotherapy doses. The graft contained, as adoptive immunotherapy, a ratio of conventional T cells (Tcons) and T regulatory cells (Tregs) that induce a Graft versus Leukemia effect with a low incidence of Graft versus Host Disease (GvHD). Methods: July 2015-October 2017: 14 AML patients (median age 62 years, 6 in 1th and 7 in 2nd complete remission, 1 in partial remission) underwent haploidentical HSCT. Composite comorbidity/age scores were 1/2 in 7 patients and 3/4 in 8. TMI/TLI target volumes were skeletal bones, major lymph node chains and spleen. TMI/TLI was delivered from day -7 to day -4, in 2 daily fractions of 1.5 Gy (TMI) and 1.3 Gy (TLI) (total doses 13.5Gy and 11.7Gy respectively). Chemotherapy: tiothepa 2.5 mg/kg on days -10 and -9; fludarabine 30 mg/m² from days -10 to -6; cyclophosphamide 15 mg/kg on days -8 and -7. Haploidentical grafts consisted of 10x10⁶/kg purified CD34+cells, 1x10⁶/kg Tcons, 2 x10⁶/kg freshly isolated Tregs. No post-transplant immunosuppression was given. Results: All patients sustained primary full-donor type engraftment and 11/14 are alive and relapse-free at a median follow-up of 18 months. Grade II-IV acute GvHD developed in 6 patients (43%) and chronic GvHD in none. Transplant-related causes of death were veno-occlusive disease (1), sepsis (1) and acute GvHD (1). Immune reconstitution was good, with peripheral blood T cells rapidly increasing. Conclusions: This innovative TMI/TLI-based conditioning with low dose chemotherapy and adoptive immunotherapy with Tcons and Tregs was efficacious as there have been no relapses to date. It was associated with low regimen-related toxicity and mortality. This exploratory analysis needs to be confirmed in a larger cohort of patients enrolled in a clinical trial.