Whether osteoarthritis (OA) is associated with alterations in the epigenetic status of anabolic factors is largely unknown. To answer the question, we investigated the DNA methylation and histone modification of SOX-9 gene promoter, a typical anabolic gene, in the articular cartilage from nine patients with femoral neck fractures without OA and from nine hip OA patients. Methylation-specific PCR (MSP) and bisulfite sequencing analysis (BSQ) showed that the methylation of SOX-9 promoter was increased in OA cartilage compared to normal cartilage. The decreased SOX-9 gene and protein expression in OA chondrocytes was reversed by the treatment of 5-azacytidine (5-AzaC), the demethylating agent. Methylation of SOX-9 proximal promoters reduced the binding affinity of transcription factors CCAAT-binding factor/nuclear factor-Y and cyclic adenosine monophosphate (cAMP) response element–binding. There was a significant increase in H3K9 and H3K27 trimethylation and a significant decrease in the acetylation of H3K9, 15, 18, 23, and 27 at SOX-9 promoters in OA chondrocytes. These findings suggest that hip OA is associated with a change in the epigenetic status of SOX-9 promoter, including increased DNA methylation and altered histone modification. © 2013 American Society for Bone and Mineral Research.