C.B-17 SCID mice were inoculated with human peripheral blood leukocytes (PBLs) from normal Epstein-Barr virus (EBV)-seropositive and -seronegative donors. Confirmation of a functioning human immune response was demonstrated by the detection of human antibody after inoculation with rotavirus, tetanus toxoid, or EBV. One group of animals inoculated with PBLs from an EBV-seropositive donor developed immunoblastic lymphomas approximately 9 weeks after transplantation. Confirmation of the species and sex of origin of the tumor cells was established using a spontaneous cell line prepared from the tumor. At passage I, the tumor-cell line (AGTI) showed 15% of the metaphases with a translocation involving chromosomes 5 and 14. A lymphoblastoid cell line (AGLCL) established from the same PBLs from the same donor at the time of inoculation of the mice had a normal female karyotype. The AGLCL and a clone of AGTI cells were analyzed for rearrangement of immunoglobulin heavy chain (IgH) genes; both cell lines showed rearrangement of both IgH alleles. The results outlined in this report suggest that a spontaneous chromosomal translocation involving chromosome 14 occurred in normal PBLs in the SCID mouse.