A series of amphiphilic and thermo-responsive block copolymers were synthesized by reductive amination betweenthe aldehyde endgroup of hydrophilic HPMC and the amine group of monoamine, diamine, or triamineJEFFAMINE as hydrophobic block. The resulting diblock, triblock and three-armed copolymers with different hydrophilic/hydrophobic ratios and block lengths were characterized by NMR, FT-IR, DOSY-NMR and SEC. Thecloud point (CP) of copolymers was determined by UV–visible spectrometer. Data show that both the geometricalstructure and the molarmass of HPMC affect the CP of HPMC-JEF copolymers. The higher the hydrophilic/hydrophobicratio, the higher the CP of copolymers which is lower than that of HPMC homopolymers. The selfassemblybehavior of the copolymers was investigated from dynamic light scattering, transmission electronmicroscopy,and critical micelle concentration (CMC) measurements. Spherical nano-micelles are obtained by selfassemblyof copolymers in aqueous solution, and the micelle size can be tailored by varying the block length ofHPMC and the geometrical structure. Three-armed HPMC-JEF copolymers present lowerCMC and smallermicellesize as compared to linear diblock and triblock ones.MTT assay evidenced the cytocompatibility of HPMC-JEF copolymers,indicating that they could be promising as drug carrier in drug delivery systems.