Integration of a drug delivery function into implantable medical devices enables local release of specific bioactives to control cells-surface interactions. One alternative to achieve this biofunctionality for bone implants is to incorporate particulate drug delivery systems (DDSs) into the rough or porous implant surfaces. The scope of this study was to assess the effects of a model DDS consisting of poly(D,L-lactide-co-glycolide) (PLGA) microspheres loaded with an anti-inflammatory drug, dexamethasone (DXM), on the response of Simian Virus-immortalized Human Fetal Osteoblast (SV-HFO) cells. The microspheres were prepared by the oil-in-water emulsion/solvent evaporation method, whereas cells response was investigated by Alamar Blue test for viability, alkaline phosphatase (ALP) activity for differentiation, and Alizarin Red staining for matrix mineralization. Cell viability was not affected by the presence of increased concentrations of polymeric microspheres in the culture media. Furthermore, in the cultures with DXM-loaded microspheres, ALP activity was expressed at levels similar with those obtained under osteogenic conditions, indicating that DXM released from the microsphere-stimulated cell differentiation. Matrix mineralization occurred preferentially around the DXM-loaded microspheres confirming that the released DXM could act as osteogenic supplement for the cells. These in vitro findings suggest that a particulate PLGA-DXM DDS may actually provide dual, anti-inflammatory and osteogenic functions when incorporated on the surface of bone implants.