OBJECTIVE Photodynamic therapy (PDT) defines the light activation of a photosensitizing compound, leading to the generation of cytotoxic, reactive oxygen species. We are investigating the unique application of PDT for diseased bone. METHODS Bioluminescent, human breast cancer cells (MT-1) were injected intracardially into athymic rats. At 2-3 weeks following injection rats developed diffuse bone metastases that were visible using an in vivo bioluminescence imaging system. Metastatic lesions within vertebrae and long bones were treated with differing regimens of 690nm laser light (25-150J) following injection of benzoporphyrin-derivative monoacid (BPD-MA) and the tumour response assayed histologically upon sacrifice. Subsequent large animal studies involved light propagation studies in porcine vertebrae and BPD-MA-PDT treatment of large primary osteosarcomas in canine. Canine were subject to high dose PDT (500J/cm). A second rat model involved bacterial infection in bone. Bioluminescent Staphylococcus aureus (S. aureus) were grown as biofilms onto wires, implanted into rat tibia and exposed to 5-aminolevulinic acid (ALA)-PDT delivered percutaneously with 635nm laser light (75J/cm(2)). Response to therapy was monitored as changes in bioluminescence signal and colony forming assay upon sacrifice. RESULTS PDT (150J) proved effective in ablating metastatic lesions within rat femur and lumbar vertebrae. Porcine studies confirmed the average depth of light penetration into trabecular bone as 0.16±0.04cm with an average incident fluence rate of 4.3mW/cm(2), however, the necrotic/non-necrotic interface extended 0.6cm out from the treatment fiber. In canine a single, high dose treatment created well-circumscribed margins of effect encompassing the entire 3-4cm osteosracoma. Finally, ALA-PDT proved effective against S. aureus biofilms in bone, although recurrent infection did occur in some. CONCLUSIONS Results support the application of PDT to the treatment of primary or metastatic lesions within bone. Secondly, ALA-PDT may be useful as a treatment for osteomyelitis with repeat or chronic treatment regimens.