The identity of the multiple myeloma (MM) precursor(s) is unknown. Our objective was to determine the myelomagenic capabilities of CD34-enriched autografts. Hematopoietic progenitor fractions from fresh or cryopreserved granulocyte-colony-stimulating factor mobilized blood from myeloma patients were obtained by sorting or enrichment, followed by RT-PCR analysis of clonotypic transcripts and/or their ability to transfer myeloma to immunodeficient mice. CD34⁺ enrichment using immunomagnetic methods comparable with those used clinically results in copurification of MM cells able to xenograft nonobese diabetic severe combined immunodeficient mice. Highly purified CD34⁺ progenitors from granulocyte-colony-stimulating factor mobilized blood of myeloma patients include, on average, 31% clonotypic MM cells. CD34⁺ progenitors also include 31% DNA aneuploid cells. For six of six MM patients, enriched progenitors were myelomagenic as measured by engraftment of clonotypic cells and/or the development of lytic bone lesions. Intrasternal injection of enriched progenitor fractions led to clonotypic cells in the femoral bone marrow and bone lesions at distant skeletal locations, confirming dissemination of myelomagenic cells. MM precursors copurify with normal hematopoietic progenitors, emphasizing the need for tumor-free grafts. Autologous MM engraftment is likely to be considerably more efficient than in a xenogeneic host, strongly suggesting that MM autografts contribute to posttransplant relapse. The xenografting myelomagenic component(s) is unlikely to be plasma cells, given the lack of morphologically identified plasma cells among enriched progenitors. Xenografting MM precursors appear to be CD34⁺CD45^low, similar to normal progenitors. Precursor function within the MM clone seems to be complex and may involve multiple components of the MM hierarchy.