We discovered that monoclonal antibodies (mAbs) specific to human β 2 -microglobulin (β 2 M) induce programmed death of myeloma and other hematological tumor cells. The mAbs exhibited potent in vitro tumoricidal activity on all 14 β 2 M/HLA-ABC-bearing myeloma, lymphoma, and leukemia cell lines and primary myeloma cells isolated from eight patients. Cell death occurred rapidly, without the need for exogenous immunological effector mechanisms. Although the expression of β 2 M on normal hematopoietic cells is a potential safety concern, the mAbs seem to be selective to tumor-transformed cells and did not induce apoptosis of normal cells, including T and B lymphocytes and CD34 + bone marrow stem cells. Furthermore, the mAbs were able to selectively kill myeloma cells without damaging normal stromal cells in their cocultures. After binding to cell surface, the mAbs mediated internalization and down-modulation of surface β 2 M and HLA-ABC molecules. The mAbs induced cell death via inhibiting PI3K/Akt and ERK, activating JNK, upregulating Bad and Bax protein expression, inducing phosphorylation of Bcl-2, and decreasing phosphorylation of Bad, all of which compromised mitochondrial integrity, leading to cytochrome c release into cytosol and activation of the caspase-9-dependent cascade. Inhibitors to pan-caspases or caspase-9, but not to caspase-8, or to JNK, and knockdown of surface β 2 M and HLA-ABC expression by β 2 M-specific siRNA, but not control siRNA, abrogated apoptosis of tumor cells induced by the mAbs. Furthermore, anti-β 2 M mAbs were also active and therapeutic in vivo; After administration subcutaneous or intraperitoneal, the mAbs substantially reduced tumor burdens and retarded tumor growth in SCID mice subcutaneously implanted with human myeloma cell lines ARP-1 or MM.1S. Therefore, such mAbs offer the potential for a novel therapeutic approach to hematological malignancies and possibly to other cancers that express surface β 2 M. This study also suggests that differential expression of β 2 M/MHC class I molecules by normal and cancer cells might be a crucial point in the sensitivity and selectivity of anti-β 2 M mAb-induced apoptosis.