The major stumbling block for most therapies against deep-seated disease, including tumours, is inefficient drug delivery. Such a concern is particularly important for osteosarcoma, the predominant form of bone cancer, and the largest cancer of its type in the paediatric age group. Pigment epithelium-derived factor (PEDF) is the most potent anti-angiogenic factor found endogenously in the body, with an increasing number of reports pointing to its direct antitumour activity. In this report, when a plasmid expressing PEDF (pPEDF) was encapsulated within two types of chitosan microparticles, anti-invasion and increased adhesion of the osteosarcoma cell line SaOS-2 was noted. Microparticles were formulated using two methods of complex coacervation and were approximately 400-600 nm in diameter. The plasmids were strongly attached to the particles which were polymorphic in shape as determined by electron microscopy. Preliminary experiments with the green fluorescent protein (GFP) reporter plasmid revealed that cells were efficiently transfected with the particles, with particles outlasting transfection with lipofectamine cationic liposomes at 5 days. In vivo, the better pPEDF microparticle resulted in a decrease in primary tumour growth, reduced bone lysis and reduced establishment of lung metastases in a clinically relevant orthotopic model of osteosarcoma. Thus, this new mode of localised gene delivery may hold promise for molecular therapy of osteosarcoma.