The exchangeable apolipoproteins are important in determining the structure/function properties of lipoproteins. These proteins typically contain varying amounts of amphipathic helices. Five model peptides, 18A, Ac- 18A-NH2, Ac-18R-NH2, 37pA, and 37aA, have been designed to investigate variations of the amphipathic α-helix structural motif on their lipid- binding properties. These include the 18-residue peptides, 18A and Ac-18A- NH2, examples of class A helices, and Ac-18R-NH2, which has the positions of acidic and basic residues interchanged relative to 18A. Three larger peptides were also studied: 36A, a dimer of 18A, 37pA and 37aA, dimers of 18A coupled by Pro (18A-Pro-18A) and Ala (18A-Ala-18A), respectively. We report here the results of a thermodynamic characterization of the binding properties of these peptides to small unilamellar vesicles of POPC. Partition coefficients, K(p), were determined by fluorescence spectroscopy and binding enthalpies, ΔH, by titration calorimetry. These parameters were used to obtain the free energies, ΔG0, and entropies, ΔS0, of binding. The results of this study indicate K(p) values on the order of 105, with interactions being enthalpically but not entropically favored in all cases. The presence of positively charged residues at the interface (18A and Ac- 18A-NH2) enhances binding but has little effect on the extent of bilayer penetration. The presence of tandem repeats decreases lipid affinities for these small, highly curved bilayers. Our results are consistent with the idea that interaction appears to be confined largely to the surface, with some degree of penetration of the hydrophobic face of the helix into the interior of the bilayer.