Cysteine-rich 61 (CYR61/CCN1), a secreted protein in bone marrow (BM) microenvironment, has diverse effects on many cellular activities such as growth and differentiation. However, the effect of CCN1 on osteoblasts (OBs) in myeloma bone disease remains unclear. In our study, the level of CCN1 in multiple myeloma (MM) patients was detected by ELISA and RT-PCR. The proliferation and differentiation of OBs from MM patients were observed after stimulated by CCN1 in vitro. The myeloma cells transduced with CYR61 gene (RPMI‑8226/CYR61) were injected in a mouse model to evaluate the efficacy of CCN1 in vivo and compare with zoledronic acid. The results showed that CYR61/CCN1 levels in BM supernatant and OBs both elevated significantly in all newly diagnosed MM patients, especially in patients without bone disease (P=0.001 and P<0.001). After 30 ng/l CCN1 stimulation for 24 h, the quantity and mineralization of OBs increased significantly in vitro (P=0.046 and 0.048). The transcription factors of Wnt pathway, runt-related transcription factor 2 (Runx2) and β-catenin were upregulated in OBs after CCN1 stimulation (P=0.012 and 0.011). After injection of RPMI‑8226 cells, bone lesions were observed obviously by microCT and histochemistry at 7 weeks. Radiographic analysis of the bones showed decreased resorption in CCN1 overexpression group and zoledronic acid group, while severe resorption in negative control. Furthermore, trabecular bone volume in CCN1 overexpression group (1.7539±0.16949) was significantly higher than zoledronic acid group (1.2839±0.077) (P=0.012). In conclusion, CCN1 can stimulate the proliferation and differentiation of OBs in vitro and contribute to bone remodeling in vivo in MBD.