Posttransplant lymphoproliferative disease (PTLD) is closely linked to primary Epstein-Barr virus (EBV) infection. A defect of EBV specific cellular immunity is postulated to play a pivotal role in the etiology of PTLD, but there is some debate as to whether EBV load in the peripheral blood of transplant patients predicts onset of PTLD or relapse after treatment. The current prospective, single-center study was undertaken to investigate the impact of therapy on EBV load in adult patients with PTLD. Fifteen patients with PTLD after solid organ transplantation were included and of these, seven had EBV-associated PTLD. All 15 patients received Rituximab as primary therapy. In cases of treatment failure or relapse after Rituximab treatment, patients received polychemotherapy according to the cyclophosphamide, vincristine, doxorubicin, and prednisone regimen. At onset of PTLD, the median EBV load in the peripheral blood of patients was higher in EBV-associated PTLD than PTLD with no associated EBV infection. After Rituximab therapy, four of seven patients with EBV-associated PTLD achieved long-lasting complete remissions. However, in two of these patients, EBV load increased to reach levels as high as those recorded at onset of PTLD. Another patient showed a dramatic decline of EBV load after the first dose of Rituximab while suffering from progressive disease. The other patient relapsed after Rituximab monotherapy, but his viral load stayed low. In total, discordance in EBV load and clinical course was observed in five of the seven patients with EBV-associated PTLD. We conclude that in adult patients with PTLD, EBV load does not correlate with treatment response and is not suitable as a predictive marker for PTLD relapse.