Osteoarthritis is a chronic degenerative joint disease that affects the whole joint, including the articulating surfaces and capsular tissues in and around the joint (Hügle and Geurts 2016). Osteoarthritis currently impacts 27 million Americans (Racine 2015). Two prominent features in osteoarthritis that are correlated with greater pain and reduced function are MRI-identified bone marrow lesions and CT-identified subchondral bone cysts (Kumar et al. 2013). At this time, the relationship between bone marrow lesions and subchondral bone cysts has not been confirmed. Nor has the nature of the tissues associated with these clinical signs been fully characterized, pointing to the need for further research to identify the composition of subchondral bone cysts as these cysts could be a potential target for therapeutic intervention. This study focused on characterizing the tissue content of subchondral bone cysts in osteoarthritic femoral heads. Osteoarthritic femoral heads were collected from male and female patients, ranging in age from 43-72 years old, who underwent total hip replacement. After surgery, the femoral heads were fixed in 4% paraformaldehyde and scanned via micro-computed tomography (MicroCT). The MicroCT images were used to identify regions in each head containing large subchondral bone cysts, the primary compressive bone, and anterior cartilage. These regions were mapped to the actual femoral head and guided the dissection of the femoral head. Samples from each of the regions were decalcified, embedded in paraffin, and cut into 5-micron-thick histological sections which were then mounted onto slides. Each section was stained in Safranin-O/Fast green and hematoxylin and eosin to visualize the tissues present. Immunohistochemistry with anti-CD31 was carried out on selected slides to identify blood vessels. The samples within all three regions of the femoral head were graded histologically for the presence of subchondral bone cysts, whether cartilage was within the cyst region, if the histological section matched its corresponding MicroCT image, if the articular cartilage was fibrillated, the presence of sclerotic bone, the presence of osteophytes, and the presence of blood vessels. It was clear that many of these samples were in later stages of osteoarthritis considering most samples exhibited all of the above characteristics, contained fibrous tissue, and had little normal fatty marrow. Typically, subchondral bone cysts presented beneath fibrillated and degenerated articular cartilage, contained fibrous tissue that was much more intensely vascularized and innervated as compared to normal fatty marrow, and was surrounded by sclerotic trabecular bone. In some cases, osteophytes also formed at the articular surface beneath areas of degenerated cartilage. Some subchondral bone cysts contained cartilage and even smooth muscle cells in addition to fibrous connective tissue. The varied location of the subchondral bone cysts shows the need for further research as to how their etiologies develop. The content of the subchondral bone cysts suggests that areas with disrupted trabeculae become intensely vascularized to allow the influx of inflammatory materials and mesenchymal stem cells to lay down fibrous tissue and thicken the surrounding trabeculae to stabilize the weakened microstructure of the femoral head. By gaining a comprehensive understanding of the pathology of osteoarthritis and of subchondral bone cysts in particular, the progression of the disease can be more firmly established and potential new treatments can be developed.