The effect of dextran sulfate and related compounds on the fusion of influenza A virus with model membranes, composed of dioleylphosphatidyl-choline and cholesterol (1:0.5), was investigated by a fusion assay based on de-quenching of fluorescence of octadecyl-rhodamine-HCl (R18). Dextran sulfate samples of molecular weight of 500 000, 8000 and 5000 were found to be potent inhibitors of the virusliposome fusion process. Polygalacturonic acid also showed anti-fusion activity, but to a lesser extent. Uncharged dextran, positively charged diethylaminoethyl-dextran, and the monomer glucosamin-1,6-disulfate were ineffective. It was shown that dextran sulfate interacts with the virus. Our results suggest that dextran sulfate binds to and inactivates the viral fusion protein. © 1990.