To assess a real-time polymerase chain reaction-based modulation of immunosuppression in patients with an increasing Epstein-Barr virus (EBV) viral load, we studied 79 paediatric allogeneic stem cell transplantations (allo-SCT) performed between January 1998 and December 2003. EBV reactivation was observed in 42 of 79 patients (53%) after a median time of 45 d from allo-SCT: 37 (88%) and five (12%) patients had received the graft from an unrelated and a related donor respectively (P = 0.001). Twenty-eight patients (67%) had a viral load > or =300 genomic copies x10(5) peripheral blood mononuclear cells (PBMC) and antithymocyte globulin was the only factor significantly associated with EBV reactivation (P = 0.001, RR 7.1). Among these 28 patients, immunosuppression was suspended and reduced in 17 and 11 patients respectively. Overall, post-transplant lymphoproliferative disease was diagnosed in one of 79 patients (1%). The pre-emptive modulation of immunosuppression in patients with EBV reactivation and a viral load > or =300 genomic copies x10(5) PBMC did not negatively influence transplant-related mortality, overall survival or event-free survival. In conclusion, EBV reactivation is frequent even in 'low risk' patients and the pre-emptive modulation of immunosuppression enables it to be managed safely, with no significant flare in graft-versus-host disease status.