The venlafaxine hydrochloride (VHL)-loaded chitosan nanoparticles were prepared by ionic gelation of chitosan (CS) using tripolyphosphate (TPP). The nanoparticles were characterized using FTIR, differential scanning calorimetry, X-ray diffraction, dynamic light scattering, transmission electron microscopy, and X-ray photoelectron spectroscopy. The effect of concentration of CS, polyethylene glycol (PEG), VHL and CS/TPP mass ratio on the particle size and zeta potential of nanoparticles was examined. The particle size of CS/TPP nanoparticles and VHL-loaded CS/TPP nanoparticles was within the range of 200-400 nm with positive surface charge. In the case of VHL-loaded nanoparticles and PEG-coated CS/TPP nano-particles, the particle size increases and surface charge decreases with increasing concentration of VHL and PEG. Both placebo and VHL-loaded CS/TPP nanoparticles were observed to be spherical in nature. PEG coafing on the surface of CS/TPP nanoparticles was confirmed by XPS analysis. Maximum drug entrapment efficiency (70%) was observed at 0.6 mg/mL drug concentration. In vitro drug release study at 37 degrees C +/- 0.5 degrees C and pH 7.4 exhibited initial burst release followed by a steady release. (C) 2009 Wiley Periodicals, Inc. J Appl Polym Sci 112: 2876-2887, 2009