Abstract:[Objective] To explore the clinical significance of detection of serum nuclear factor erythroid 2-related factor 2 (NFE2L2) in nontraumatic osteonecrosis of the femoral head (NONFH). [Methods] A total of 78 patients with NONFH (the necrosis group) and 80 healthy controls (the normal group) admitted to Linyi People's Hospital from August 2021 to February 2022 were included in this study. Serum NFE2L2 levels in both groups were detected by ELISA. The difference of serum NFE2L2 level between necrotic group and normal group was compared. The levels of serum NFE2L2 in necrotic group were compared in stratified manner according to different factors. The correlation between serum NFE2L2 level and other clinical data was analyzed, and the significance of serum NFE2L2 diagnosis of NONFH was evaluated by drawing ROC diagnostic curve. [Results] Serum NFE2L2 level in necrotic group was significantly higher than that in normal group [(289.2±130.7) pg/ml vs (173.7±75.7) pg/ml, P<0.001]. Although there was no significant difference in the level of serum NFE2L2 between different causes and different sides in the necrotic group (P>0.05), the serum NFE2L2 level after femoral head collapse was significantly higher than that before femoral head collapse [(320.0±131.2) pg/ml vs (199.8±79.4) pg/ml, P=0.004]. In addition, the serum NFE2L2 level increased significantly with the progression of ARCO stages, with statistically significant differences among the different stages (P<0.05). In term of correlation analysis, the serum NFE2L2 level was significantly positively correlated with ARCO stage and VAS score (P<0.05), whereas significantly negatively correlated with Harris score (P<0.05). In term of ROC analysis, the area under curve (AUC) of serum NFE2L2 level for the diagnosis of NONFH was of 0.769. [Conclusion] Serum NFE2L2 level is significantly elevated in patients with NONFH, which correlates with the severity of NONFH and may be a potential serum marker for the diagnosis of NONFH.