In this study, we created a clinically relevant model using NOD/SCID mice engrafted with human bone fragments in both right and left flanks, and show that the human bone implants are viable and functional for more than 6 mo. To investigate the growth and metastatic behavior of breast cancer, human primary breast tumor specimens were transplanted into human bone grafts under only the right flanks of the human-bone NOD/SCID mice. Some of the engrafted tumors proliferated extensively with massive neo-vascularization and also metastasized to the initially tumor-free left flank bone grafts. We show for the first time that this mouse model can be used to distinguish between primary breast tumors that do or do not proliferate and metastasize to contralateral human bone implants that were initially tumor-free.