Introduction: Craniofacial traumatic lesions frequently lead to debilitating and challenging consequences, as a result of infectious processes which make the immediate and successful surgical regenerative treatment difficult and/or impossible. Objectives: In the present work, it is aimed the development and biological characterization of a poly methyl methacrylate (PMMA)-based minocycline delivery system, to be used as a space maintainer within craniofacial staged regenerative interventions. Materials and methods: Developed PMMA systems were characterized regarding solid state characteristics and assayed in vitro for anti-bacterial and anti-inflammatory activity, and cytocompatibility with human bone cells. Results: Drug release profile revealed the maintenance of minimum inhibitory concentrations against Staphylococcus aureus, slime-producer-S. epidermidis and Escherichia coli, up to 72 hours. Further, controlled minocycline release decreased the release of pro-inflammatory mediators from activated macrophages and enhanced the functionality of osteoblastic cells, within in vitro models. Discussion: PMMA-based minocycline delivery system allowed for an adequate drug release profile, supporting a sustained antibacterial activity against relevant pathogenic bacteria commonly associated with craniofacial bone infections. Further, a sustained anti-inflammatory activity and enhanced bone cell response were verified. Conclusions: The developed PMMA systems, with controlled release of minocycline, allowed for an effective antibacterial activity and enhanced cytocompatibility, supporting a prospective utility for staged craniofacial reconstructive approaches. Clinical implications: The developed PMMA system displays an effective antibacterial activity and expectedly primes tissue healing through inflammation modulation and enhancement of osteoblastic response. Funding: This work was partly supported by the FCT grant UID/DTP/04138/2013. Keywords: minocycline, bone, PMMA, drug delivery system, biological characterization and cytocompatibility