Biodegradable, dextran-based ion-exchange microspheres (IE-MS) have been used for localized delivery of anticancer drugs and chemosensitizers. Because of their hydrophilic nature, the IE-MS release their payload quickly. The purpose of this work was to develop an IE-MS system that could provide a broad range of release rates for in vitro and in vivo applications. Sulfopropylated dextran microspheres (SP C25 MS) were surface-modified by acylation. These hydrophobically modified sulfopropylated dextran microspheres (HM-MS) were further coated with the cationic acrylic polymer Eudragit RL100 (EU-MS). The changes in chemical composition after the surface modification and coating were characterized by X-ray photoelectron spectroscopy. The effects of the modification and coating on the surface hydrophobicity, equilibrium swelling, surface morphology, and drug loading capacity were investigated. The HM-MS showed little change in swelling and functionality, despite significantly increased affinity to oil and carbon content on the surface. The coated microspheres (EU-MS) exhibited a profoundly decreased swelling ratio, an even higher affinity to oil, a higher loading capacity, and a lower drug release rate. Through further coating of the EU-MS with different amounts of corn oil, the rate of drug release could be tailored to cover a relatively wide range. These results suggest that a versatile delivery system with various release profiles can be prepared by a combination of hydrophobic modification, polymer coating, and oil coating.