We have investigated the adsorption of hydrophobically end-capped poly(ethylene glycol) (HE-PEG) with carbon number (m) in the hydrocarbon end chain ranging from 0 to 16 onto phospholipid membrane by use of quartz crystal microbalance with dissipation (QCM-D), surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). QCM-D and SPR studies show that the hydrophobic interaction between HE-PEG chains and the lipid membrane increases with the hydrocarbon chain length. At a low HE-PEG concentration, the adsorption cannot induce a vesicle-to-bilayer transition until the carbon number is up to 16. However, at a high HE-PEG concentration, the adsorption results in a vesicle-to-bilayer transition at m > or = 12. ITC measurements demonstrate that enthalpy change (DeltaH) for the mixing of lipid vesicles with HE-PEG chains is too small to be detectable when m is less than 12. However, DeltaH changes from positive to negative as the carbon number increases from 12 to 16, indicating that the HE-PEG insertion increases with its hydrocarbon end-chain length. The present study reveals that the hydrophobic interaction between the lipid membrane and HE-PEG chains as well as the osmotic pressure drive the adsorption and insertion of such polymer chains.