Salicylates and several other nonsteroidal anti-inflammatory drugs (NSAIDs) that are commonly employed in the treatment of osteoarthritis effectively decrease joint pain and increase mobility. Results from in vitro studies indicate that, in addition, some of these compounds affect proteoglycan metabolism of articular cartilage. Data from in vivo studies suggest that salicylate administration may accelerate articular cartilage damage in several animal models of osteoarthritis. At in vitro concentrations comparable to those that are achieved in the synovial fluid of patients treated with the drug, several NSAIDs suppress proteoglycan synthesis by the chondrocyte. Salicylate has been shown to inhibit the enzymes involved in the early stages of chondroitin sulfate biosynthesis. These NSAID-related effects on chondrocyte metabolism appear unrelated to inhibition of prostaglandin synthetase, and are much more profound in osteoarthritic cartilage than in normal cartilage, due to enhanced uptake of NSAIDs by the osteoarthritic cartilage. Depletion of matrix proteoglycans appears to be a major factor in the increased vulnerability of chondrocytes in degenerating cartilage to effects of NSAIDs. Some NSAIDs may be bound to matrix components. If similar changes occur in the cartilage of patients with arthritis treated with NSAIDs, despite the symptomatic improvement that these drugs produce, cartilage degeneration could be accelerated.