Several nonsteroidal antiinflammatory drugs which are cyc.axygenase inhibitors (e.g., salicylates, fenoprofen, ibuprofen) have been shown to suppress proteoglycan synthesis by normal joint cartilage in vitro. We examined the effect of benoxaprofen, a longacting proprionic acid derivative which inhibits lipoxygenase in addition to causing moderate cyclooxygenase inhibition. When added to the culture medium in concentrations comparable with those obtainable in serum of patients treated with the drug (e.g., 10 and 50 pglml), benoxaprofen increased proteoglycan synthesis in slices of normal canine knee cartilage to 126% and 135%, respectively, of control levels. These concentrations of the drug augmented net protein synthesis to 154% and 12396, respectively, of control levels. Incorporation of 3H glucosamine into 9-aminoacridine precipitable material was increased by benoxaprofen, showing that it stimulates net proteoglycan synthesis, and not merely sulfation. At concentrations of either 10 or 50 pglml, the drug had no effect on proteoglycan catabolism or on the ability of proteoglycans to interact with cartilage hyaluronic acid to form macromolecular aggregates. Nordi-From the Rheumatology Division,