Hyaluronan (HA) is a high molecular weight glycosaminoglycan found in large amounts in the skin, joints, and other organs. Previous studies have shown that HA stimulates neutrophil functions both in vitro and in vivo. The object of this study was to test the hypothesis that HA administration subcutaneously might reduce the number of bacterial infections in humans with an increased susceptibility to such infections. For this purpose we have studied 29 patients with chronic bronchitis and recurrent acute exacerbations of their disease. The patients were randomly separated into two groups. One group had HA for 6 mo followed by 6 mo of placebo, and the other group started with placebo treatment followed by HA. The treatment periods occurred during two consecutive winter periods. HA-treated patients had significantly fewer acute exacerbations (p = 0.01) than did placebo-treated patients. Likewise the consumption of antibiotics and other signs of bacterial infections were reduced. In the crossover study the placebo-treated patients again had much higher numbers of acute exacerbations than did the HA-treated patients (p < 0.0001). It is concluded that HA reduces the number of infectious exacerbations in patients with chronic bronchitis, possibly by enhancing cellular host defense mechanisms. HA is a new endogenous substance that can be used to stimulate host defense reactions and reduce the need of antibiotics. Before being recommended for clinical use, however, our results should be confirmed by further studies.