Following marrow transplantation in both patients and animals, cells containing donor nuclei have been detected in a variety of nonhematopoietic tissue. Whether this phenomenon represents transdifferentiation of marrow-derived cells, infiltration of blood cells, or cell fusion is still controversial. In muscle, where cell fusion occurs during normal myogenesis, fusion of marrow-derived cells with resident myotubes is a likely explanation. We tested 8 subpopulations of human bone marrow for their ability to fuse with mouse C2C12 myoblast cells. Relatively high fusion efficiency was observed with marrow stromal cells whereas hematopoietic cells, including populations enriched for stem cells, progenitor cells, and monocytes were refractory to fusion. Mouse myotubes containing human nuclei also contained transcripts for human muscle-specific genes. Injection in vivo of human stromal cells expressing green fluorescent protein (GFP) into the regenerating tibialis anterior muscle of nonobese diabetic-severe combined immunodeficient (NOD/SCID) beta 2m(-/-) mice resulted in regenerating mouse muscle fibers expressing GFP. These data suggest that marrow-derived cells contribute to myogenesis through fusion and that stromal cells are better fusion partners than hematopoietic cells.