The objective of this article was the synthesis and characterization of protein-based microspheres able to respond to pH changes using methacrylated gelatin hydrolyzed, methacrylic acid sodium salt and N,N'-methylenebisacrylamide as protein monomer, pH-responsive functional monomer, and cross-linking agent, respectively. Reverse-phase suspension polymerization as synthetic technique was adopted and, varying the molar ratios of the reagents in the polymerization feed, three different hydrogels were obtained. These were characterized by scanning electron microscopy and dimensional analyses to verify the spherical shape and the dimensional distribution. Then, Fourier transform infrared spectra and water uptake experiments at acidic and neutral pH were performed, in order to verify the copolymerization of all the components and the pH-responsivity, respectively. Finally, after loading of the microspheres with a common nonsteroidal anti-inflammatory drug, such as diclofenac sodium salt, drug release experiments in simulated gastric fluid (pH 1) and in simulated intestinal fluid (pH 7) were performed, confirming the suitability of the obtained materials as drug delivery devices. (C) 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012