The synthesis and characterization of a new amphiphilic grafted hydroxypropyl cellulose (HPC) containing polycholesteryl methacrylate side chains has been described. First, HPC was converted to an atom transfer radical polymerization (ATRP) macroinitiator by the reaction of hydroxyl groups of HPC with 2-bromoisobutyryl bromide. Then, the hydrophobic homo- and random-copolymer side chains, HPC-g-PMMA, and HPC-g-(PMMA-ran-PCMA)s were grafted from a HPC core using methyl methacrylate (MMA) and cholesteryl methacrylate (CMA) monomers at 80 °C in toluene. The obtained graft copolymers were characterized via conventional spectroscopic methods. Thermogravimetric analysis (TGA) and differential scanning calorimetric (DSC) in combination were used to investigate the thermal properties of the obtained compounds. Graft polymers depicted decreased thermal stability in comparison with that of HPC due to the reduced crystallinity. Being compared with HPC-g-PMMA, it was found that the glass transitions of modified HPC-g-(PMMA-ran-PCMA)s values moved to lower temperatures and diminished with the increase of the cholesteryl groups’ amount. These compounds achieved solubility’s in a variety of organic solvents, therefore, nanoparticles formed in water/ethyl acetate using the emulsion-diffusion technique and polyvinyl alcohol as the emulsifier. The transmission electron microscopy (TEM) image of obtained nanoparticles showed particle sizes of ＜150 nm and a uniform shape. In conclusion, hydrophobically modified HPC have a potential to serve as a new platform for biodegradable and biocompatible nanocarriers.