Background: The relative importance and interrelationship of risk factors for posttransplantation lymphoproliferative disorder are poorly understood. Methods: The prospective pretransplantation serologic testing for Epstein- Barr virus of all nonrenal solid organ transplant recipients at our institution made it possible to assess the relative risk for posttransplantation lymphoproliferative disorder in seropositive and seronegative recipients. Results: Fourteen cases of lymphoproliferative disorder were identified in the first 389 consecutive transplant recipients (288 liver, 44 heart, 20 lung, 37 kidney-pancreas) undergoing transplantation from 1985 to 1992 (mean follow-up 33 months). The incidence rates of lymphoproliferative disorder (per 100 person-years) during the first 2 years after transplantation (a period in which all cases occurred) were 1.4 for liver, 2.0 for heart, 6.2 for lung, and 5.2 for kidney-pancreas transplant recipients and were significantly different between liver and lung (p = 0.005) and liver and kidney-pancreas (p = 0.002) groups. Of 367 seropositive patients, lymphoproliferative disorder developed in only three. The incidence rate ratios between seronegative and seropositive recipients were as follows: 76 ([95% confidence interval; 46, 144], p = 0.0000) for any form of lymphoproliferative disorder and 145 ([60, 347], p = 0.0000) for fatal or brain forms. The incidence rate of lymphoproliferative disorder was significantly higher for seronegative recipients who required antilymphocyte antibody therapy for rejection than for those who received none. Conclusions: The high intrinsic risk for lymphoproliferative disorder in the Epstein-Barr virus seronegative patient, which is amplified by higher levels of immunosuppression, may, in some instances, preclude transplantation.