The pathogenesis of necrosis of the femoral head (NFH) remains elusive. Limited studies were conducted to investigate the molecular mechanism of hip articular cartilage damage in NFH. We conducted genome-wide gene expression profiling of hip articular cartilage with NFH. Hip articular cartilage specimens were collected from 18 NFH patients and 18 healthy controls. Gene expression profiling of NFH articular cartilage was carried out by Agilent Human 4x44K Gene Expression Microarray chip. Differently expressed genes were identified using the significance analysis of microarrays (SAM) software. Gene Ontology (GO) enrichment analysis of differently expressed genes was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Significantly differently expressed genes in the microarray experiment were selected for quantitative real-time PCR (qRT-PCR) and immunohistochemical validation. SAM identified 27 differently expressed genes in NFH articular cartilage, functionally involved in extracellular matrix, cytokines, growth factors, cell cycle and apoptosis. The expression patterns of the nine validation genes in qRT-PCR were consistent with that in proteinaceous extracellular matrix (false discovery rate (FDR) = 3.22 × 10(-5)), extracellular matrix (FDR = 5.78 × 10(-5)), extracellular region part (FDR = 1.28 × 10(-4)), collagen (FDR = 3.22 × 10(-4)), extracellular region (FDR = 4.78 × 10(-4)) and platelet-derived growth factor binding (FDR = 5.23 × 10(-4)). This study identified a set of differently expressed genes, implicated in articular cartilage damage in NFH. Our study results may provide novel insight into the pathogenesis and rationale of therapies for NFH.