Multiple myeloma causes approximately 10% of all hematologic malignancies. We have previously shown that human T cells expressing chimeric NKG2D receptors (chNKG2D) consisting of NKG2D fused to the CD3ζ cytoplasmic domain secrete proinflammatory cytokines and kill human myeloma cells. In this study, we show chNKG2D T cells are effective in a murine model of multiple myeloma. Mice with established 5T33MM-green fluorescent protein tumors were treated with one or two infusions of chNKG2D T cells. Compared with mice treated with T cells expressing wild type (wt)NKG2D receptors, a single dose of chNKG2D T cells increased survival, with half of the chNKG2D T-cell-treated mice surviving long term. Two infusions of chNKG2D T cells led to tumor-free survival in all mice. ChNKG2D T cells were located at sites of tumor growth, including the bone marrow and spleen after intravenous injection. There was an increase in activated host T cells and NK cells at tumor sites and in serum interferon-γ after chNKG2D T-cell injection. Surviving mice were able to resist a rechallenge with 5T33MM cells but not RMA lymphoma cells, indicating that the mice developed a protective, specific memory response. These data demonstrate that chNKG2D T cells may be an effective adoptive cellular therapy for multiple myeloma.