Avascular necrosis of the femoral head (AVNFH) is a progressive, multifactorial, and challenging clinical disease that causes hip pain and loss of hip joint function. Till now, the pathogenesis of AVNFH was not fully understood. In this study, we characterized cartilage protein profiles of patients with AVNFH and identified the potential proteins involved in the progress of AVNFH using proteomics technique.Proteins from the cartilage of 6 patients (3 AVNFH patients and 3 fracture patients) were extracted and identified using label-free proteomics. AVNFH-responsive proteins were compared with those of the fracture patients and duly identified. Bioinformatics analyses including gene ontology (GO), KEGG, and STRING were performed to identify the functions of AVNFH-responsive proteins.A total of 1512 proteins were identified from cartilage tissues of the patients. Compared to fracture patients, 255 significantly changed proteins were identified in cartilage tissues of patients with AVNFH. Functional categorization indicated that the significantly changed proteins were mainly involved in ECM-receptor interaction, focal adhesion, and glycolysis pathways. Interestingly, adipocyte enhancer-binding protein 1, cytoskeleton-associated protein 4, and ASPN protein were dramatically decreased, however, anti leukoproteinase, erythrocyte membrane protein, and lysozyme c were highly increased in patients with AVNFH.The current proteomic results suggest that ECM-receptor interaction and focal adhesion related proteins contribute to development of AVNFH. To our knowledge, this is firstly reported proteomic study on cartilage tissues of patients with AVNFH. The marker proteins including caveolae-associated protein 3 and procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 could help us to understand the pathogenesis of AVNFH.© 2022 The Author(s). Published by IMR Press.