Allogeneic hematopoietic cell transplant is a potential curative therapy for acute lymphoblastic leukemia (ALL). Delineating the graft-versus-leukemia (GVL) effect as a function of graft-versus-host disease (GVHD) offers the potential to improve survival. We examined 5215 transplant recipients with ALL reported to the Center for International Blood and Marrow Transplant Research registry. Overall survival (OS) was compared according to the presence and severity of GVHD and evaluated in 3 cohorts: 2593 adults in first or second complete remission (CR1/CR2), 1619 pediatric patients in CR1/CR2, and 1003 patients with advanced (CR $3 or active disease) ALL. For patients in CR1/CR2, development of acute GVHD (aGVHD) or chronic GVHD (cGVHD) was associated with lower risk of relapse than no GVHD (hazard ratio [HR], 0.49-0.69). Patients with advanced ALL developing grades III and IV aGVHD or cGVHD were also at lower risk of relapse (HRs varied from 0.52 to 0.67). Importantly, adult and children in CR1/CR2 with grades I and II aGVHD without cGVHD experienced the best OS compared with no GVHD (reduction of mortality with HR, 0.83-0.76). Increased nonrelapse mortality accompanied grades III and IV aGVHD (HRs varied from 2.69 to 3.91) in all 3 cohorts and abrogated any protection from relapse, resulting in inferior OS. Patients with advanced ALL had better OS (reduction in mortality; HR, 0.69-0.73) when they developed cGVHD with or without grades I and II aGVHD. In conclusion, GVHD was associated with an increased GVL effect in ALL. GVL exerted a net beneficial effect on OS only if associated with low-grade aGVHD in CR1/CR2 or with cGVHD in advanced ALL.