OBJECTIVE We examined the effects of manganese (III) meso-tetrakis (diethyl-2-5-imidazole) porphyrin, a metalloporphyrin antioxidant (MPA), on neural tissue radiation toxicity in vivo and on tumour cell radiosensitivity in vitro. METHODS MPA was administered directly into the right lateral ventricle of young adult, male Sprague-Dawley rats (0 or 3.4 microg) 3 h before treatment with a single fraction, 100 Gy radiation dose delivered to the left brain hemisphere. The effects of treatment on radiation responses were assessed at different time points following irradiation. RESULTS MPA treatment prior to brain irradiation protected against acute radiation-induced apoptosis and ameliorated delayed damage to the blood-brain barrier and radiation necrosis, but without producing a discernible increase in tissue superoxide disumtase (SOD) activity. In vitro, MPA pretreatment protected against radiation-induced apoptosis in primary neuronal cultures and increased clonogenic survival of irradiated rat glioma C6 cells, but had no discernible effect on radiation-induced DNA double-strand breaks. MPA, a low molecular weight SOD mimic, significantly increased mitochondrial SOD activity in C6 cells, but not total cellular SOD activity. MPA up-regulated C6 expression of heme-oxygenase 1 (HO-1), an endogenous radioprotectant, but had no effect on HO-1 levels in human astrocytoma U-251 cells, human prostatic carcinoma LNCaP cells, or primary rat brain microvascular endothelial cells in vitro, nor on brain tissue HO-1 expression levels in vivo. CONCLUSIONS Metalloporphyrin antioxidants merit further exploration as adjunctive radioprotectants for cranial radiotherapy/radiosurgery applications, although the potential for tumour protection must be carefully considered.