The concentration of lipid peroxides in the plasma and synovial fluid of 65 arthritic patients was determined using a new ion-pairing reverse phase HPLC technique. Patients with rheumatoid arthritis receiving only non-steroidal anti-inflammatory drugs, had a significantly higher mean concentration of lipid peroxides in synovial fluid samples (162 +/- 22.0 micrograms/l) than osteoarthritic patients (40.0 +/- 8.0 micrograms/l, p less than 0.0001). Mean concentrations in both groups correlated strongly with the level of beta-glucuronidase activity as a measure of lysosomal enzyme release (r = 0.71, p less than 0.0001). Contrary to previous reports by investigators using less specific methods, we were unable to demonstrate any increase in plasma levels of lipid peroxides in the rheumatoid patient. Treatment of rheumatoid arthritis with D-penicillamine was associated with a significant reduction of lipid peroxide levels (83.2 +/- 11.5 micrograms/ml, p less than 0.002), suggesting that this drug may function as an oxygen radical scavenger in the joint cavity. These results give further support to the concept of oxygen-free radicals playing an important role in the pathogenesis of chronic inflammatory disorders.