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Osteoarthritis of the knee is a leading cause of chronic disablity in the United States. It is a heterogeneous condition that causes pathogenic changes that are presumably irreversible. In many cases, knee pain is often progresive and leads the patient to seek medical attention. Pharmacologic and nonmedicinal treatments are, in most cases, only modestly successful in relieving pain. Hyaluronic acid (HA) funtions as the backbone of the proteoglycan aggregates necessary for the functional integrity of articular cartilage of the knee. Two drugs made up of HA derivatives have recently become available for patients in whom simple analgesics and conservative nonpharmacologic therapy have failed. This article reviews the epidemiology, pathogenesis, diagnosis, and medical management of osteoarthritis of the knee, with an emphasis on the physiologic and pharmacologic mechanisms of HA. Health care providers may administer HA via intra-articular injection in primary care, rheumatologic or orthopedic settings, or they may refer their patients to specialists for consultation.