Thioredoxin peroxidase (TPx) is an antioxidant protein that limits the activity of reactive oxygen species (ROS). We cloned the cDNA encoding the mouse homolog of TPx from an E14.5 brain cDNA library and analyzed its distribution and function in murine tissues. Comparison of the amino acid sequence of mouse TPx with those of other species revealed that TPx was highly conserved across all species. Mouse TPx had broad tissue distribution, but its expression was especially marked in cells that metabolize oxygen molecules at high levels such as erythroid cells, renal tubular cells, cardiac and skeletal muscle cells, and certain types of neurons. Levels of increased expression of TPx in the brain were coincident with regions known to be especially sensitive to hypoxic and ischemic injury in humans. Models of erythroid differentiation and neuronal survival were employed to study the function of TPx. Murine erythroleukemia cells (MEL cells) increased TPx transcription when in a chemically differentiated state. Furthermore, expression of mouse TPx in PC12 pheochromocytoma cells prolonged their survival in the absence of nerve growth factor (NGF) and serum, indicating that TPx could promote neuronal cell survival. We propose that TPx contributes to antioxidant defense in erythrocytes and neuronal cells by limiting the destructive capacity of oxygen radicals. These findings identify a novel gene that appears to be relevant to hypoxic brain injury and may be of importance in development of new approaches to abrogate the effects of ischemic- and hypoxic-related injury in the central nervous system (CNS).