A rare case of multiple myeloma associated with severe Coombs-positive hemolytic anemia is described. A 60-year-old woman was hospitalized for acute hemolysis due to an IgG warm autoantibody with pan-agglutinin specificity. Serum and urine electrophoresis revealed the presence of a monoclonal IgGk protein and a BJk protein, respectively. Bone marrow aspirates showed diffuse infiltration with plasma cells, and skeletal survey revealed lytic lesions in the skull and diffuse osteoporosis. Treatment with prednisone, and subsequently with melphalan, cyclophosphamide and vincristine resulted in hematological improvement within two weeks. A reduction of paraprotein below 50% of the initial levels was found after six months of therapy.