Polymeric (Ethylcellulose: Eudragit (R) RS100) microspheres containing aceclofenac was formulated by oil-in-water (o/w) single emulsion solvent evaporation method using response surface methodology. The amount of PVA and polymers in combination were selected as formulation variables and the speed of the stirrer as a process variable. The resultant microspheres were characterized for their size, morphology, encapsulation efficiency (E.E.), and drug release. The physicochemical characteristics of microspheres were assessed operating field emission scanning electron microscopy, Fourier transform infrared spectroscopy (FTIR), and X-ray powder diffractometry (XRPD). The PVA and speed were identified as the significant factors determining the encapsulation efficiency of the microspheres. The E. E. range was from 60.86 +/- 0.76% to 84.07 +/- 0.88%, enhanced with the decrease in the amount of PVA and increase in speed of stirring. Optimized formulation of microspheres was prepared using optimal process variables setting in order to evaluate the optimization capability of the models generated according to IV-optimal design. The optimized microspheres formulation containing aceclofenac showed E. E. of 84.94 +/- 1.91 with small error value (0.88). The microspheres were found to be discrete, spherical with smooth surface. The absence of interaction between drug and polymer was confirmed by FTIR spectroscopy. The XRPD revealed the dispersion of drug within microspheres formulation. Sustained drug release profile (minimum; 18.55% - 62.79%; maximum) in 12 h was achieved by a combination of polymers. The results demonstrate that these microspheres could be promising delivery system to sustain the drug release and improve the encapsulation efficiency thus prolong drug action and achieve the highest healing effect with minimal gastrointestinal side effect. (C) 2014 The Society of Powder Technology Japan. Published by Elsevier B. V. and The Society of Powder Technology Japan. All rights reserved.