Both purified hyaluronic acid (HA) and bovine synovial fluid react with OCl‐, the major oxidant produced by the myeloperoxidase (MPO)/H2O2/Cl‐ system, resulting in a decrease in their specific viscosity. This reaction is inhibited in the presence of excess methionine. H2O2 alone decreases the viscosity of HA, presumably by the Fenton reaction, in the absence (but not in the presence) of the iron chelator, diethyltriaminepentacetic acid (DETAPAC). In the presence of DETAPAC, incubation of HA with the complete MPO/H2O2/Cl‐ system lowered the viscosity of HA. Analysis of 3H‐HA exposed to OCl‐ by gel filtration chromatography indicated that cleavage of HA occurred only at higher OCl‐ concentrations. We suggest that the reduction in viscosity of HA by the MPO/H2O2/Cl‐ system may be due to a combination of oxidative cleavage and changes in the conformation of the molecule. We speculate that the changes in the molecular size of rheumatoid synovial fluid HA may be due to the action of the neutrophil MPO/H2O2/Cl‐ system.