This study aimed to investigate whether idiopathic osteonecrosis of the femoral head (ONFH) is associated with alterations in the microstructure, histological characteristics, and transcriptomic signature in the trabecular region of the femoral head. For this purpose, we obtained trabecular bone explants from the femoral head and the intertrochanteric region of patients with idiopathic ONFH and age- matched patients with primary osteoarthritis (OA). Trabecular bone from the femoral head of ONFH patients showed lower trabecular thickness, bone volume fraction and degree of anisotropy, and a higher percentage of empty lacunae than bone samples from the intertrochanteric region of the same patients and from the femoral head of the OA group. The transcriptome analysis identified a substantial number of genes exclusively regulated in the femoral head of ONFH patients. Among these genes, we found that those highly expressed around the necrotic lesion were involved in cell division and immune response. By contrast, downregulated genes were mainly involved in cell adhesion, angiogenesis and bone formation, such as those encoding collagen type I, bone sialoprotein and several bone morphogenetic proteins. These data add new insights into mechanisms involved in the pathophysiology of idiopathic ONFH.