The solubilization of amphotericin B (AB) by synthetic bilayer fragments from dioctadecyldimethylammonium bromide (DODAB) or sodium dibexadecylphosphate (DHP) dispersions in water is described. Drug solubilization was followed from dynamic light scattering and optical spectroscopy. The very low solubility of AB in water permits the determination of size distributions for AB aggregates in water and a comparison to the one in the presence of DODAB or DHP nanosized bilayer fragments. There is a disappearance of the large drug aggregates upon its incubation with the nanosized bilayer fragments. Light absorption spectra for AB in a poor solvent (water), in a good organic solvent (dimethyl sulfoxide: methanol 1 : 1), and in different lipid dispersions also show that solubilization strictly depends on the presence of bilayer fragments. AB is poorly soluble in dispersions formed of entire closed vesicles of DODAB, DHP, phosphatidylcholine, or asolecithin. Solubilization can be understood from the AB chemical structure and an increased hydrophobicity at the borders of bilayer fragments. These hydrophobic borders interact with the polyenic moiety of the antibiotic leaving the hydroxylated moiety free to face the surrounding water. Inexpensive, synthetic bilayer fragments offering a very large area of hydrophobic nanosurfaces well dispersed in water open new perspectives for controlled release of AB and other toxic and water-insoluble drugs.