The hyaluronic acid (HA) content of articular cartilage was studied in early experimental osteoarthritis (OA) in 16 normal dogs. The anterior cruciate ligament in the right knees of the dogs was transected; their left knees served as sham operated controls. The animals were killed at 7 and 14 weeks postsurgery. Although their total hexuronate, and thus proteoglycan, content remained unaltered during the period of study, the different weight-bearing areas of the OA knees displayed a progressive and significant decrease in HA content. We found no differences in the molecular weight and in vitro aggregating capacity of the HA molecules from OA cartilage versus those from control cartilage. This early relative depletion of HA could contribute significantly to the biochemical alterations of OA cartilage. Furthermore, it appears to be a good parameter for the differentiation of changes related to OA and changes related to aging.