Azlactone-functionalized microporous polystyrene resins were synthesized by suspension polymerization of styrene, divinylbenzene and N-(p-vinylbenzyl)-4,4- dimethylazlactone (VBM). A fractional factorial design of experiments (DOE) has been used to evaluate the influence of several parameters (factors) on the physical and chemical properties (responses) of the resins. Six factors were considered: (i) the organic/aqueous phase ratio, (ii) the amount of the functional monomer N-(p-vinylbenzyl)-4,4-dimethylazlactone, (iii) the amount of stabilizer, (iv) the amount of initiator, (v) the stirring speed, and (vi) the equilibration time. The process responses were the yield of polymerization, the diameter of the beads and their polydispersity, their swelling ratio in dichloromethane and the accessibility ratio of the immobilized azlactone sites. This methodology enables the determination of an optimal combination of the six factors to synthesize beads in high yield (92%) with remarkable properties for SPOS applications (azlactone sites loading = 1.57 mmol/g, swelling ratio in dichloromethane = 5.0 mL/g and 100% accessibility ratio). (C) 2007 Wiley Periodicals, Inc.