Hyaluronic acid (HA) is a major component of human synovial fluid, providing the rheologic properties (elasticity and viscosity) that enable the synovial fluid to perform lubricating and shock-absorbing functions within the healthy joint. Over the last 2 decades, HA preparations have become established in intra-articular therapy of osteoarthritis (OA), particularly OA of the knee. Existing HA preparations, both cross-linked and non-cross-linked, are all administered by courses of multiple injections, and all have been associated with variable success rates. The clinical profile of an HA preparation is inextricably linked to the product's physicochemical properties. For example, the molecular structure of the HA affects the intra-articular residence time, which should in turn influence the duration of action post-injection. Non-animal stabilized hyaluronic acid (NASHA) is a new-generation HA preparation, produced wholly from non-animal sources. NASHA is stabilized using a carefully controlled cross-linking process, which increases the intra-articular residence time from hours to weeks. This facilitates single-injection treatment for OA without affecting the biocompatibility of HA. This review evaluates the properties of NASHA, including the available clinical data, in the context of previously developed HA preparations.