Post-transplantation lymphoproliferative disorder (PTLD) is a widely recognized and often catastrophic complication of organ transplantation. The incidence of PTLD after lung transplantation ranges from 6.2 to 9.4% and is two-fold higher than that seen after organ transplantation of other organs. Primary Epstein-Barr virus (EBV) infection is a major risk factor for PTLD, but the incidence of PTLD in EBV seronegative (EBV-) patients seems to vary with type of organ transplant. The goal of this study was to quantify the risk of PLTD based on pre-lung transplantation EBV serostatus in lung transplant patients. Pre- and post-lung transplant serostatus was defined in 80 patients, and our six cases of PTLD occurred in this group. Six of 94 lung transplant patients (6.4%) who survived > 1 mo developed PTLD. All cases of PTLD involved thoracic structures at presentation and occurred in the first post-operative year. Patients who were EBV- before lung transplant were much more likely to develop PTLD than those who were seropositive (EBV+) (five of 15 [33%] versus one of 60 [< 2%], p < 0.001). Consistent with the prevailing adult (donor) EBV+ rate (85%), two of our EBV-patients remained EBV-after lung transplant. Therefore, the rate of PTLD was 42% in those with primary EBV infection. As compared with EBV-patients that remained tumor-free, those who developed PLTD had similar levels of immunosuppressants and doses of anti-viral therapy. We conclude that PLTD occurs predominantly in EBV-naïve patients (risk approximately 1/3). EBV-patients should be monitored more closely after lung transplantation and, possibly, managed with lower immunosuppression. Our data also suggest that anti-viral therapy alone does not decrease the incidence of PTLD in high risk patients, PTLD can be successfully treated in most cases, and EBV-naïve patients should not be excluded from lung transplant because their risk of death from PTLD is < 15%.