Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in the case of post-transplantation relapse. We aimed to compare treatment strategies in 334 consecutive children with acute leukemia relapse or progression after SCT in a recent 10-year period. Data could be analyzed in 288 patients (157 ALL, 123 AML and 8 biphenotypic AL) with a median age of 8.16 years at transplantation. The median delay from first SCT to relapse or progression was 182 days. The treatment consisted of chemotherapy alone (n = 108), chemotherapy followed by second SCT (n = 70), supportive/palliative care (n = 67), combination of chemotherapy and donor lymphocyte infusion (DLI; n = 30), or isolated reinfusion of donor lymphocytes (DLI; n = 13). The median OS duration after relapse was 164 days and differed according to therapy: DLI after chemotherapy = 385 days, second allograft = 391 days, chemotherapy = 174 days, DLI alone = 140 days, palliative care = 43 days. A second SCT or a combination of chemotherapy and DLI yielded similar outcome (hazard ratio (HR) = 0.85, P = 0.53) unlike chemotherapy alone (HR = 1.43 P = 0.04), palliative care (HR = 4.24, P<0.0001) or isolated DLI (HR = 1,94, P<0.04). Despite limitations in this retrospective setting, strategies including immunointervention appear superior to other approaches, mostly in AML.