In this study, the biocompatibility of a calcium phosphate (CaP) cement incorporating poly (D,L‐lactic‐co‐glycolic acid) (PLGA) microparticles was evaluated in a subcutaneous implantation model in rats. Short‐term biocompatibility was assessed using pure CaP discs and CaP discs incorporating PLGA microparticles (20% w/w) with and without preincubation in water. Long‐term biocompatibility was assessed using CaP discs incorporating varying amounts (5, 10, or 20% w/w) and diameter sizes (small, 0–50 μm; medium, 51–100 μm, or large, 101–200 μm) of PLGA microparticles. The short‐term biocompatibility results showed a mild tissue response for all implant formulations, irrespective of disc preincubation, during the early implantation periods up to 12 days. Quantitative histological evaluation revealed that the different implant formulations induced the formation of similar fibrous tissue capsules and interfaces. The results concerning long‐term biocompatibility showed that all implants were surrounded by a thin connective tissue capsule (<10 layers of fibroblasts). Additionally, no significant differences in capsule and interface scores were observed between the different implant formulations. The implants containing 20% PLGA with medium‐ and large‐sized microparticles showed fibrous tissue ingrowth throughout the implants, indicating PLGA degradation and interconnectivity of the pores. The results demonstrate that CaP/PLGA composites evoke a minimal inflammatory response. The implants containing 20% PLGA with medium‐ and large‐sized microparticles showed fibrous tissue ingrowth after 12‐ and 24‐weeks indicating PLGA degradation and interconnectivity of the pores. Therefore, CaP/PLGA composites can be regarded as biocompatible biomaterials with potential for bone tissue engineering and advantageous possibilities of the microparticles regarding material porosity. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2008