Cigarette smoke has been implicated in the pathogenesis of a variety of diseases that affect connective tissues. The effect of the gas phase of cigarette smoke on hyaluronic acid was investigated in vitro. The smoke markedly reduced the chain length of purified hyaluronic acid as assessed by both viscometry and gel chromatography. The hyaluronate exposed to smoke, nevertheless, could aggregate proteoglycans, although the viscosity of the aggregates was lower than in those formed with the unexposed material. The degradation of the hyaluronate was a rapid phenomenon and was inhibited by dimethylsulfoxide, a known scavenger of hydroxyl radicals. We conclude that free radicals in the gas phase of cigarette smoke degrade hyaluronic acid in vitro.