The purpose of this study was to synthesize and characterize amphiphilic β-cyclodextrins modified on the primary face with substituents of varying chain lengths (C6 and C14) and bond types (ester or amide). We also aimed to evaluate the potentiality of the new amphiphilic β-cyclodextrins as excipients for the preparation and optimization of nanocapsules without using surface-active agents. Amphiphilic β-cyclodextrin derivatives were characterized by 1H-nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, mass spectroscopy, differential scanning calorimetry, and elemental analysis. Nanocapsules prepared by nanoprecipitation were characterized by particle size and zeta potential determination and freeze fracture followed by transmission electron microscopy. The appropriate amphiphilic β-cyclodextrin and its optimum concentration to be used were determined. Formation and characteristics of the nanocapsules were highly dependent on the structural properties of the modified cyclodextrin, its behavior in the oil–water interface and the viscosity and miscibility of the organic solvent with water. Physical stability after 5-month storage was also evaluated. The results indicated that derivatives with 6C aliphatic chains on the primary face proved to be the most efficient among the amphiphilic β-CDs in this study. They avoid the use of surfactants in parenteral formulations of nanocapsules. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91: 1214–1224, 2002