We recently identified macrophage inflammatory protein 1-α (MIP-1α) as a factor produced by multiple myeloma (MM) cells that may be responsible for the bone destruction in MM (1). To investigate the role of MIP-1α in MM bone disease in vivo, the human MM–derived cell line ARH was stably transfected with an antisense construct to MIP-1α (AS-ARH) and tested for its capacity to induce MM bone disease in SCID mice. Human MIP-1α levels in marrow plasma from AS-ARH mice were markedly decreased compared with controls treated with ARH cells transfected with empty vector (EV-ARH). Mice treated with AS-ARH cells lived longer than controls and, unlike the controls, they showed no radiologically identifiable lytic lesions. Histomorphometric analysis demonstrated that osteoclasts (OCLs) per square millimeter of bone and OCLs per millimeter of bone surface of AS-ARH mice were significantly less than in EV-ARH mice, and the percentage of tumors per total bone area was also significantly decreased. AS-ARH cells demonstrated decreased adherence to marrow stromal cells, due to reduced expression of the α₅β₁ integrin and diminished homing capacity and survival. These data support an important role for MIP-1α in cell homing, survival, and bone destruction in MM.