Hyaluronan-phospholipid interactions have been studied in vitro by negative staining and rotary shadowing electron microscopy. Hyaluronan (HA) molecules of different molecular weights (around 170,000; 740,000, and 1.9 x 10(6) Da) were added to phospholipid suspensions (DPPC or egg lecithin) that were in the form of either unilamellar particles or multilamellar vesicles. Suspensions were then gently stirred and incubated at different temperatures from 24 hr up to 7 days. After 24 hr, at temperatures just above the melting point of the phospholipid used, both unilamellar particles and multilamellar vesicles were already shown to change their organization in the presence of HA, giving rise to the formation of (1) huge perforated membrane-like structures lying on the substrate; (2) 12-nm-thick "cylinders" (rollers) with a tendency to aggregate and to form sheets. These structures were seen only in the presence of high-molecular-weight HA, whereas low-molecular-weight HA (170 kDa) induced fragmentation of liposomes and formation of a few short rollers. These data show that phospholipids and HA interact and suggest they may also do so in vivo within the joint cavity, where both chemical species are present, giving rise to complexes which might exhibit peculiar lubricating and protective properties. It is also proposed that such interactions may not be as efficient in arthritic joints, where HA is degraded to low-molecular-weight fragments.