Nineteen renal allograft recipients developed B-cell lymphoproliferative diseases. Clinically there were two groups: a) young patients (mean age, 23 years) who presented soon (mean, 9 months) after transplantation or antirejection therapy with fever, pharyngitis, and lymphadenopathy resembling infectious mononucleosis, and b) older patients (mean age, 48 years) who presented later (mean, 6 years) after transplantation with localized tumor masses. Histologically, the diseases were classified as polymorphic diffuse B-cell hyperplasia (PDBH) or polymorphic B-cell lymphoma (PBL). Immunologic cell typing revealed either polyclonal or monoclonal B-cell proliferations. Malignant transformation of polyclonal proliferations in two patients was suggested by the finding of clonal cytogenetic abnormalities. Epstein-Barr virus (EBV) specific serology, staining of biopsy specimens for the Epstein-Barr nuclear antigen, and EBV DNA molecular hybridization studies implicated EBV as the cause of both PDBH and PBL. Acyclovir, an antiviral agent that blocks EBV replication in vitro, inhibited oropharyngeal shedding of EBV and caused complete remission in four patients with polyclonal B-cell proliferations. The monoclonal tumors were acyclovir resistant. We suggest that surgical treatment, radiotherapy, or chemotherapy may be more appropriate therapy in selected patients with acyclovir resistant tumors. Therapeutic decisions require not only documentation of the viral etiology of these tumors, but also immunologic and cytogenetic analysis to determine the stage of tumor evolution in individual patients.