The introduction of single-agent rituximab has markedly changed the approach to therapy of patients with post-transplantation lymphoproliferative disorder (PTLD), but response to treatment varies substantially between patients. In the current report, we analyze long-term efficacy of single-agent rituximab in 60 patients and present factors predictive of progression-free and overall survival. Twelve months after completing first-line treatment, 34 of 60 patients (57%) had progressive disease, resulting in a median progression-free survival of 6.0 months at a median follow-up of 16.3 months. Using multivariate Cox regression analysis, the following factors were identified as significantly predictive of overall survival: age at diagnosis, performance status, lactate dehydrogenase (LDH), and time from transplantation to PTLD. Stage of disease and Epstein–Barr virus association of PTLD did not influence overall survival. LDH and time from transplantation to PTLD were also predictive of progression-free survival. The international prognostic index was shown to be of limited predictive value in these patients, but a PTLD-specific prognostic index separated low-, intermediate-, and high-risk patients with high significance: 2-year overall survival rates after first-line treatment with single-agent rituximab were 88, 50, and 0%, respectively. Thus, prognostic indices can be useful tools for prediction of treatment outcome and for the development of risk-adapted treatment strategies in patients with PTLD and may also provide the basis for interstudy comparisons.