Abstract: Objective To investigate the diagnosis significance of serum cystatin C (Cys-C), β₂-microglobulin (β₂-MG) and creatinine (Cr) in multiple myeloma (MM). Methods The serum levels of Cys-C, β₂-MG, Cr, uric acid (UA) and urea of 43 newly diagnosed MM patients and 30 healthy persons in Hainan Nongken Nada Hospital and Nanfang Hospital from February 2010 to January 2014 were detected using Hitachi 7600 automatic biochemical analyzer. Receiver operating characteristic curve (ROC) was used to evaluate the value of Cys-C, β₂-MG and Cr in the diagnosis of MM. Results The level of Cys-C in patients with MM (2.06±0.82) mg/L was significantly higher than in the control group (0.71±0.18) mg/L (P＜ 0.01), and it was significant positive correlated with β₂-MG (r=0.523, P＜ 0.05). During Durie-Salmon stage, the level of CysC (3.14±1.38) mg/L in phase Ⅲ was significantly higher than that in phase Ⅱ (1.35±0.16) mg/L and phase Ⅰ (0.97±0.18) mg/L (P＜ 0.01). The levels of serum Cr and β₂-MG in phase Ⅲ showed statistically significant difference comparing with that in phase Ⅰ and Ⅱ(P＜ 0.05). Cys-C level of serum light chain (2.75±1.01) mg/L was significantly higher than that of no secretion (1.49±0.53) mg/L in different immune classification (P＜ 0.05), and β₂-MG level of IgA type serum (7.48±4.52) mg/L was significantly higher than that of no secretion (5.37±2.64) mg/L (P＜ 0.05). Receiver operating characteristic curve analysis showed that area under curve (AUC) and 95% confidence interval of CysC (0.912, 95%CI: 0.891-0.960) were higher than that of the β₂-MG (0.853, 95%CI: 0.821-0.894) and Cr (0.741, 95%CI: 0.702-0.795), the difference was statistically significant (P＜ 0.05). Conclusion Cys-C can be used as one of indexes for the early diagnosis of MM patients with renal damage, which is better than β₂-MG and Cr, and it also can help with clinical stage, tumor burden and prognosis.