Mefenamic acid (MA) spherical agglomerates (SAs) were prepared with various polymethacrylates having different permeability characteristics (Eudragit RS 100, Eudragit RL 100 and Eudragit L 100) and also with combination of Eudragit RS 100 and Eudragit L 100 in different ratios. SAs were prepared by spherical crystallization method using ethanol/dichloromethane solvent (crystallization) system. The influence of various formulation factors on the encapsulation efficiency, as in vitro drug release, and micromeritic properties was investigated. Target release profile of MA was also drawn. The yields of preparation and the encapsulation efficiencies were high for all formulations. The shape and surface characteristics of SAs were observed by a scanning electron microscope. The particle sizes are in the range of 0.219 +/- 0.1 to 0.482 +/- 0.25 mm (mean +/- confidence interval t(95%)). In addition, histological studies showed that the administration of MA in SAs containing Eudragit RS/L provided a distinct tissue protection in the stomach and duodenum. Differential scanning calorimetry and X-ray diffraction of powder studies showed that MA particles crystallized in the presence of polymethacrylates did not undergo structural modifications.