Immunodeficient humans are at very high risk of developing Epstein-Barr virus (EBV)-induced lymphomagenesis. Severe combined immunodeficient mice (SCID) have been shown to develop lymphoproliferative disease (LPD) following transfer of peripheral blood leukocytes (PBL) with latent EBV. To study mechanisms of lymphomagenesis, we compared results of engraftment of PBL from normal donors and immunodeficient donors with X-linked lymphoproliferative disease (XLP). Graft-versus-host disease (GVHD) developed in 6 of 10 SCID mice 4 to 8 weeks following transfer of PBL from normal donors. In contrast, none of 9 mice engrafted with PBL from XLP patients with T-cell defects showed GVHD. LPD developed in mice regardless of the immune competence of the donors. The expression of EBV-encoded proteins, results of immunophenotyping, and karyotyping of the LPD lesions revealed lethal oligoclonal LPD owing to transfer of latent EBV in B cells in mice engrafted with PBL from seropositive donors. Polyclonal LDP developed in mice engrafted with PBL from seronegative patients which were infected with B95-8 virus 6 weeks after transfer of the cells. This model is useful for investigating mechanisms of EBV-induced LDP in immunodeficient patients.