We examined the therapeutic effect of high molecular weight hyaluronic acid (HA) on the progression of joint pain and cartilage degeneration in a rabbit osteoarthritis (OA) model. The OA model was induced by partial meniscectomy. In the time course study, cartilage degeneration was assessed at 3, 7 and 14 days after operation. In the therapeutic study, HA or loxoprofen (LOX) was administered for 14 days beginning four days after operation (after the onset of knee pain and cartilage degeneration). Knee pain was assessed by weight distribution on the hind paw, and cartilage damage and MMP production in the joints were evaluated 18 days after surgery. In the time course study, severe cartilage damage was found three days after operation. In the treatment study, weight-bearing on the injured paw in the control group decreased with time from four days after the operation. However, HA or LOX treatment beginning four days after the operation normalized the reduced hind paw weight distribution, and PGE(2) production was inhibited by HA treatment and LOX treatment. HA significantly inhibited cartilage degeneration, whereas LOX did not. HA also suppressed the production of MMP in joints. Treatment of HA after the onset of cartilage destruction and pain showed a cartilage protective effect as well as an analgesic effect.