Objective To understand the correlation of expression levels of serum stromal cell-derived factor 1α (SDF-1α), osteoprotegerin (OPG) and β2microglobulin (β2-MG) in patients with multiple myeloma (MM) with or without myeloma bone disease (MBD). Methods Eighty patients with MM who were admitted to the Affiliated Hospital of Inner Mongolia Medical University from January 2014 to June 2017 were selected; all of the patients met the international diagnostic criteria for MM. According to the symptoms such as bone pain, the patients were divided into group with MBD (45 cases) and group without MBD (35 cases). Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum levels of SDF-1α and OPG, and radioimmunoassay was used to detect the expression of MM major prognostic indicator β2-MG. The MBD score was evaluated in 45 patients selected by random number table after sacroiliac joint X-ray and three-dimensional bone reconstruction. The χ 2test was used to compare the categorical variables; the two independent sample t-test was used to compare the continuous variables that conformed to the normal distribution between two groups, and the Pearson method was used for the correlation analysis. Results The expression level of serum SDF-1α in the group with MBD was significantly higher than that in the group without MBD [0.31±0.17) pg/ml vs. (0.18±0.06) pg/ml], and the difference was statistically significant (t ＝-4.21, P < 0.001). The expression level of serum OPG in the group with MBD was significantly lower than that in the group without MBD [(0.73±0.50) pg/ml vs. (1.08±0.31) pg/ml], and the difference was statistically significant (t＝ 3.62, P< 0.001). Pearson analysis showed that β2-MG level in the group was positively correlated with SDF-1α level (r＝ 0.84, P< 0.001), and negatively correlated with OPG level (r＝ -0.48, P<0.001). The β2-MG level in the group without MBD did not show a correlation with the SDF-1α and OPG levels. Conclusions In the serum of patients with MBD, the expression levels of β2-MG and SDF-1α are increased, and the expression level of OPG is decreased. SDF-1α and OPG may be new clinical biochemical indicators for diagnosis, treatment and prognosis assessment in MBD.