Human multiple myeloma (MM) xenografts have been difficult to establish in athymic mice. We examined the feasibility of establishing human MM xenograft growth in SCID mice following subcutaneus (sc) injection of 1-2x107 cells from the human plasma cell dyscrasia (PCD) cell lines RPMI 8226 and ARH-77. SC tumors emerged in 67% (6/9) of RPMI 8226- and 6 of 6 ARH-77-injected mice after a latency period of 9-54, days and reached 19-35 mm in diameter before the mice were sacrificed. RPMI 8226 and ARH-77 primary tumor DNA hybridized positively with the human genome probe Alul-(Blur8), confirming successful engraftment of the human MM cell lines. The RPMI 8226 xenografts comprised predominantly of plasmacytoid cells that expressed the relevant cytoplasmic immunoglobulin (cIg) light chain isotype. Xenografted RPMI 8226 cells also expressed CD10 (CALLA; 44% reactive cells), CD38 (OKTI0; 69%), CD5 (49%), and reacted with the MM monoclonal antibody MM4 (39%). Human MM growth appeared to be localized subcutaneously for both RPMI 8226 and ARH-77 xenografts. There were no detectable metastatic foci in kidney, brain, heart, or bone marrow. Whereas diffuse plasma cell infiltrates were observed in spleen, GI tract, and lung biopsies of tumor-bearing mice, these infiltrates were of host origin according to immunophenotyping and DNA analyses. Neither the originating RPMI 8226 line nor its SCID mouse xenograft expressed Epstein Barr virus (EBV) genome sequences. These observations indicate that both EBV- (RPMI 8226) and EBV+ (ARH-77) cell lines can be successfully propagated in SCID mice. These xenografts retained the antigenic features of human MM, and may be useful for assessing immunotherapeutic approaches for this disease.