B chronic lymphocytic leukemia (CLL) cells were transferred into mice with severe combined immunodeficiency (SCID). Leukemia cells injected into the peritoneal cavity of these animals may survive for at least 10 weeks in vivo. In contrast, leukemia cells do not survive for long periods when injected intravenously. Despite the longevity of CLL cells injected i.p., these cells apparently do not migrate to other lymphoid tissues. Eight to sixteen weeks after receiving CLL cells, SCID mice develop human IgG autoantibodies to human red blood cells and/or high serum levels of human Ig. Soon thereafter, these animals develop lethal human B-cell tumors. In contrast to the original CLL cells, these human B-cell tumors are CD5-negative, have genomic DNA of Epstein-Barr virus (EBV), express antigens associated with latent EBV infection and have distinctive Ig gene rearrangements by Southern. We conclude that bystander B cells may generate tumors in CLL-reconstituted SCID mice that emulate the EBV-associated lymphoproliferations noted in SCID mice reconstituted with normal human PBL.