Nitric oxide is an important mediator in Osteoarthritis (OA), and causes apoptosis and dedifferentiation in articular chondrocytes. Protein kinase C alpha is involved in modulating apoptosis and dedifferentiation of articular chondrocytes induced by nitric oxide. Hyaluronic acid is widely used in the treatment of osteoarthritis and exerts significant chondroprotective effects. The exact mechanisms of its chondroprotective action are not yet fully elucidated. The present study was performed to investigate the effects and mechanisms of hyaluronic acid in NO-induced apoptosis and dedifferentiation of chondrocytes. The ratio of apoptotic cell and cell viability was surveyed by TUNEL, MTT assay and flow cytometry. The expression of aggrecan, type II collagen, and PKC alpha were determined by real-time PCR and Western blot. The expression changes of caspase-3 and bcl-2 was detected by Western blot. The mitochondrial membrane potential (Delta Im) was evaluated by Rhodamine-123 fluorescence. HA reduces the TUNEL positive cell, nuclei fragment and the impairment of Delta Im. NO-induced chondrocyte dedifferentiation was blocked by HA, which restores expression of aggrecan and type II collagen of chondrocytes and cell viability. HA can block inhibition of PKC-alpha by NO. Our results show that HA blocks NO-induced apoptosis and dedifferentiation of articular chondrocytes by modulation of Delta Im and PKC alpha.