To determine the graft-versus-leukemia effect after hematopoietic stem cell transplantation (HSCT), we studied 199 patients with acute lymphoblastic leukemia who underwent transplantation at Huddinge University Hospital between 1981 and 2001. Seventy-four patients were in first complete remission (CR1), and 125 were in later stages of the disease. Most patients had an HLA-identical sibling donor. Conditioning consisted mainly of total body irradiation and cyclophosphamide, and graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. Acute GVHD developed in 143 patients and chronic GVHD in 67. The 5-year probability of relapse and relapse-free survival (RFS) were 32% and 49%, respectively, in patients in CR1, as compared with 53% and 33% in those with more advanced disease. In the multivariate risk factor analysis of relapse, we found that the absence of chronic GVHD (P<.001), absence of herpes simplex virus infection after HSCT (P=.003), combination prophylaxis with methotrexate and cyclosporine (P=.01), and >6 weeks from the diagnosis to CR (P=.025) were independent risk factors for relapse after HSCT. Factors associated with a better relapse-free survival were chronic GVHD (P<.001), ABO blood group mismatch (P=.006), younger patient age (P=.01), and an HLA-matched donor (P=.01). The association between herpes simplex virus infection and a low frequency of relapse is a new observation and may indicate that viral antigens play a role in the induction of an antileukemic effect.