Human chondrocytes in three-dimensional culture were incubated for up to 20 days in the presence of etodolac, a nonsteroidal anti-inflammatory drug which penetrates readily into the synovial fluid. Even at an etodolac concentration of 80 micrograms/ml, DNA synthesis, proteoglycan synthesis, and type-II collagen synthesis were unchanged. Collagenase production was also unaffected by etodolac (60 micrograms/ml). In contrast, prostaglandin E2 production was reduced by 84% in the presence of 60 micrograms/ml of etodolac. The 80 micrograms/ml concentration is 5 times that found in the serum of subjects treated with 200 mg of etodolac twice a day for 6 days, and 33 times the concentration in synovial fluid of arthritic patients treated with etodolac 200 mg twice a day for 7 days. These in vitro results indicate that anti-inflammatory levels of etodolac may not damage articular cartilage in vivo.