We report here the first evidence for the interaction of poly(ethylene glycol) (PEG) with hyaluronan (HA) in aqueous solutions. PEG-HA complexes (K-app 45,000 +/- 8000 M-1) contained about 3.3 +/- 0.1 of ethylene glycol units per disaccharide of HA. The carboxyl of the D-glucuronic acid and the amide of the N-acetyl-D-glucosamine did not participate in PEG binding. Similar experiments performed with dextran and monosaccharides showed that multiple free primary hydroxyls regularly distributed along the polysaccharide chain are necessary for PEG binding. Another novelty of our study is contraction of HA upon PEG binding. The effect was observed with HA in solution or adsorbed on positively charged liposomes. The thickness of the HA layer on the liposomes decreased 2-fold upon PEG addition. HA compaction induced by PEG may underlie the changes in the plasma membrane properties and resealing of mechanical injuries induced by Pluronics.