Post-transplant lymphoproliferative disorder (PTLD) following allogeneic hematopioetic stem cell transplantation (HSCT) is a fulminant disease with high mortality. The objective of this study was to determine risk factors in PTLD following HSCT in order to identify high-risk patients for surveillance, prophylaxis and treatment. Five hundred and fifty-three HSCT patients transplanted at Karolinska University Hospital in Huddinge between 1996 and 2004 were investigated retrospectively and 14 cases of PTLD were identified. Diseased patients were evaluated concerning transplantation procedure, PTLD diagnosis, treatment and outcome. Factors significant in univariate analysis were included in logistic regression multivariate analysis. The incidence of PTLD was 2.5% and the median onset of PTLD was 78 days post-transplantation. Only two PTLD patients survived. The most common therapy was anti-B-lymphocyte antibodies. Statistical analysis showed HLA mismatch (p< 0.001), mismatch in Epstein-Barr virus (EBV) serology (p< 0.001) and splenectomy (p= 0.006) to be risk factors associated with PTLD. Indeed, among 387 patients with no risk factors only one developed PTLD (0.26%). Patients with one risk factor had a probability of developing PTLD of 8.2% and those with two risk factors, a probability of 35.7%. We propose a strategy for dealing with PTLD. Patients without risk factors need not be monitored routinely. HSCT patients with one or more risk factors should be monitored weekly by polymerase chain reaction of EBV DNA, and for patients with two or more risk factors EBV-specific cytotoxic T-lymphocytes should be held in readiness before initiating the transplantation procedure.