The purpose of this study was to form indomethacin (IND)-loaded poly(methyl methacrylate) (PMMA) microspheres having an extended drug release profile over a period of 24 h. Microspheres were prepared by solvent evaporation method using sucrose stearate as a droplet stabilizer. When PMMA was used alone for the preparation of microspheres, only 44% of IND could be released at the end of 8 h. Triacetin was added to PMMA, as a minor phase, and the obtained microspheres showed a high yield process with recovery of 89.82% and incorporation efficiency of 102.3%. A desired release profile lasting 24 h was achieved. Differential scanning calorimetry (DSC) analysis showed that IND was found to be in an amorphous state in the microspheres. Fourier transform infrared (FT-IR) and nuclear magnetic resonance (1H NMR) spectra suggested that there might be a hydrogen bond present between the IND hydroxyl group and PMMA. No interaction between triacetin and IND or PMMA as the formation of secondary bonds was observed. The release enhancement of IND from microspheres was attributed to the physical plasticization effect of triacetin on PMMA and, to some extent, the amorphous state of the drug. © 2010 Elsevier B.V. All rights reserved.