The purpose of this study is to explore and develop biodegradable scaffold for bone regeneration or tissue engineering with the capacity of controlled drug delivery. Ceftazidime as a model drug was encapsulated in ethyl cellulose (EC) microspheres, which were subsequently incorporated in a hydroxyapatite/polyurethane (HA/PU) composite scaffold to generate an antibiotic drug delivery system. HA/PU scaffolds had an interconnected pore network with an average porosity of about 83%. The presence of microspheres in the composite scaffolds was confirmed by scanning electron microscopy. The drug‐loaded EC microspheres were uniformly distributed in the HA/PU scaffold matrix and showed no significant effect on the pore structure of the scaffold. Incorporation of microspheres into scaffolds significantly reduced the initial burst release, and the system exhibited a sustained release of the model drug for up to 60 days. Moreover, the scaffold with drug‐loaded microspheres was proved to be an effective drug delivery system with good cytocompatibility and antibacterial properties. The novel drug‐loaded microsphere/scaffold composites developed in this study are promising to serve as vehicles for controlled drug delivery in bone regeneration or bone tissue engineering. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2010.