This study deals with the preparation of temperature-sensitive chitosan/hydroxypropyl cellulose-graft-poly-acrylamide (CS/HPC-g-PAAm) blend microspheres as a controlled drug release system. For this purpose, HPC-gPAAm copolymers of hydroxypropyl cellulose (HPC) with acrylamide (AAm) were synthesized using cerium (IV) ammonium nitrate as initiator. The HPC-g-PAAm copolymers were characterized by using Fourier transform infrared spectroscopy (FTIR), elemental analysis, and differential scanning calorimetry (DSC). Lower critical solution temperatures (LCST) of the synthesized copolymers were determined. Temperature-sensitive blend microspheres of HPC-g-PAAm and chitosan were prepared by emulsion cross-linking method using glutaraldehyde (GA) as a cross-linker in the hydrochloric acid catalyst (HCl) and they were used to achieve controlled release of amoxicillin trihydrate (AMX), an antibiotic drug. The microspheres were characterized by DSC, X-ray diffraction (X-RD), and FTIR spectroscopy. In addition, surfaces of empty and drug-loaded microspheres were examined by scanning electron microscopy (SEM). The effects of variables such as CS/HPC-g-PAAm ratio, drug/ polymer ratio, amount of cross-linker, and reaction time of grafting on AMX release were investigated at three different pH environments (1.2, 6.8, 7.4) at 25 degrees C, 37 degrees C, and 50 degrees C. The release results showed that the microspheres had temperature sensitivity and the AMX release was slightly more controlled by especially increasing graft yield (%).