Introduction. The prevalence of symptomatic osteoarthritis (OA) in the knee is 11–11% compared to 3.4–4.4% in the ankle. In addition to this, 70% of ankle arthritis is post-traumatic while the vast majority of knee arthritis is primary OA. Several reports have previously implicated biochemical differences in extracellular matrix composition between these joint cartilages; however, it is unknown whether there is an inherent difference in their transcriptome and how this might affect their respective functionality under load, inflammatory environment etc. Therefore, we have analysed the transcriptome of ankle and knee cartilage chondrocytes to determine whether this could account for the lower prevalence and altered aetiology of ankle OA. Methods. Human full-depth articular cartilage was taken from the talar domes (n=5) and the femoral condyles (n=5) following surgical amputation. RNA was extracted and next generation sequencing (NGS) performed using the NextSeq®500 system. Statistical analysis was performed to identify differentially regulated genes (p adj < 0.05). Data was analysed using Integrated Pathway Analysis software and genes of interest validated by quantitative PCR. Results. 809 genes were differentially expressed in this NGS study: 781 genes were significantly up-regulated and 27 significantly down-regulated in ankle cartilage with respect to knee. Preliminary analysis has identified several pathways which are differentially regulated including ‘inflammation mediated by cytokines’, ‘glutamate receptor pathway, ‘heterotrimeric-G-protein signalling pathways’, ‘WNT signalling’ and ‘integrin signalling’. Discussion. This is the first report identifying genes that are differentially expressed in ankle cartilage compared to the knee. Validation is currently being performed to ascertain the importance of these gene changes and correlation with their protein expression in the different joints. An understanding of the inherent biological differences in the cartilage between these two joints will provide invaluable insight into why the ankle is relatively spared from primary OA and the majority of ankle arthritis occurs following trauma