© 2018 ISEH – Society for Hematology and Stem Cells Relapse of acute leukemia (AL) after allogeneic hematopoietic cell transplantation (Allo-HCT) entails a dismal prognosis. In this scenario, donor lymphocyte infusions (DLIs) and second Allo-HCT are two major approaches. We compared outcomes of AL patients treated for relapse with DLI or second Allo-HCT after receiving debulking therapy. In total, 46 patients were included in the study; 30 (65%) had acute myeloid leukemia and 16 (35%) had acute lymphoblastic leukemia. The median age was 38 years (range 4–66). Twenty-seven patients received a second Allo-HCT and 19 patients received DLI. The median follow-up of the cohort was 273 days (range 9–7013). Overall survival (OS), disease-free survival (DFS), nonrelapse mortality, and cumulative incidence (CI) of relapse were calculated from DLI or second Allo-HCT date. In univariate analysis, second Allo-HCT was associated with higher OS (p = 0.021) and a trend to higher DFS (p = 0.097) and CI of relapse (p = 0.094) on univariate analysis. However, multivariate analysis showed comparable outcomes between DLI and second Allo-HCT, with the time interval to relapse before DLI or second Allo-HCT the only statistically significant factor with an impact on OS and DFS. Within the DLI cohort, T-cell-depleted Allo-HCT was associated with higher OS (p = 0.003) and DFS (p < 0.001) and lower CI of relapse (p = 0.002) than T-cell-replete Allo-HCT. Overall, in this cohort of AL patients, second Allo-HCT and DLI associated similar outcomes. As in other relapse studies, the length of remission (time to relapse) was identified as a factor with statistical impact on survival. Further studies are warranted.