The interaction of aqueous dimyristoyl-phosphatidylcholine liposomes with the polypeptides gramicidin A, poly-l-lysine, valinomycin, and gramicidin S was investigated by means of laser-Raman spectroscopy. Auxiliary data were obtained with differential scanning calorimetry. Studies were carried out over the temperature range of 0-50 °C, encompassing the gel phase, the transition region, and the liquid crystalline phase of the liposomes. Conformational changes in the phospholipid molecules were investigated by measuring the intensity of the 1062-cir-1 Raman band which is assigned to C-C stretching vibrations of trans segments. Three different types of phospholipid-polypeptide interactions were indicated by the observed Raman data. They are interpreted as (a) orderly penetration of the phospholipid bilayer by a hydrophobic polypeptide; (b) polar interactions involving primarily the head groups of the phospholipid; and (c) disorderly hydrophobic binding between a polypeptide and the hydrocarbon domain of the phospholipid. © 1979, American Chemical Society. All rights reserved.