Background and purpose: Osteopontin (OPN) is a glycophosphoprotein that is expressed by numerous human cancer cells. The function of OPN in skeletal modeling and remodeling, bone resorption, angiogenesis and tumor cell metastasis and progression through binding with integrin and CD44 receptors were studied. Our purpose of the study was to detect the level of osteopontin(OPN) and CD44 variant isoforms(CD44v6) in multiple myeloma (MM) patients, and to explore the relationship between OPN and CD44v6 with the progress of MM. Methods: 32 MM patients were admitted to our hospital from Sep. 2007 to Dec. 2008. The patients were divided into two groups, group A (untreated and relapsed MM patients) and B (stable MM patients), and the control group including 15 subjects were the benign anemia patients or healthy people who suffered bone fracture. Bone marrow mononuclear cells (MNCs) and bone marrow stromal cells (BMSCs) from MM patients and subjects were investigated as potential OPN and CD44v6 producers. The level of OPN and CD44v6 of the conditioned media from MM patients and subjects were analyzed by ELISA. Results: The OPN level in group A (19 cases) was significantly higher than group B (13 cases) and control group (P<0.05). The CD44v6 level of 14 patients in group A was significantly higher than that of 10 cases in group B and control group (P<0.05); The OPN level of MM patients was correlated with the level of CD44v6 (r=0.52, P=0.000), the percentage of plasma cells in the bone marrow (r=0.74, P=0.000), M protein (r=0.53, P=0.014), and β2-microglubin (r=0.62, P=0.002). Conclusion: The increase of OPN and CD44v6 is associated with progress and pathogenesis of MM,and may be involved with tumor burden, stage and tumor invasion.