The presence of a graft-versus-tumor effect has been well established in leukemia but not in multiple myeloma. A 40-year-old patient with myeloma refractory to standard chemotherapy and autologous transplantation received a matched unrelated T-cell-depleted transplant after conditioning with fractionated total-body irradiation, thiotepa, and cyclophosphamide. This procedure resulted in a transient and incomplete response with evidence of rapidly progressive disease within 2.5 months posttransplantation. The patient then received a small number of donor peripheral blood (PB) mononuclear cells (CD3 cells 1.2 x 10(6)/kg) without any further cytotoxic therapy. A complete remission was attained, lasting now for more than 14 months. The procedure was associated with severe acute and subsequently limited chronic graft-versus-host disease (GVHD). This report provides the first direct evidence of a graft-versus-myeloma effect after allogenic transplantation.