Abstract:[Objective] To explore the role of secreted frizzled-related proteins 5 (SFRP5) in non-traumatic osteonecrosis of the femoral head (NONFH). [Methods] A total of 71 patients who were diagnosed of NONFH in Linyi People's Hospital from September 2023 to January 2024 were selected as the necrosis group, while other 68 healthy persons who underwent regular health physical examination and were matched in gender and age with the necrosis group were selected as the normal group. Serum SFRP5 levels in the two groups were detected by ELISA. General data between the two groups were compared, while the serum SFRP5 in the necrotic group were compared according to different factors (ARCO stage, side, etiology, etc.), and ROC curve was drawn to analyze the diagnostic value of serum SFRP5 for NONFH. [Results] The necrotic group had significantly lower serum SFRP5 than the healthy group [(16.9±12.7) pg/mL vs (32.9±17.2) pg/mL, P<0.001]. In the necrosis group, the SFRP5 was significantly lower in the patients who had femoral head collapse than those without collapse (P<0.05), whereas which was not statistically significant between the patients with bilateral necrosis and those with unilateral necrosis (P>0.05). However, the SFRP5 was significantly decreased with the increasing of the ARCO stages (P<0.05). In term of pairwise correlation analysis, SFRP5 was significantly positively correlated with Harris score (P<0.05), while significantly negatively correlated with ARCO stage and VAS score (P<0.05). In term of ROC analysis, the SFRP5 predicting NONFH was with sensitivity of 70.4% and specificity of 80.9% and area under curve (AUC) of 0.787. [Conclusion] Serum SFRP5 decreases with the progression of non-traumatic osteonecrosis of the femoral head, and SFRP5 may be a potential serum marker for the diagnosis of NONFH