Neuronal apoptosis is an important process of secondary brain injury which is induced by neurochemical signaling cascades after traumatic brain injury (TBI). Present study was designed to investigate whether FOS-like antigen 1 (Fra-1) is involved in the neuronal apoptosis. Western blot analysis and immunohistochemistry in a rat TBI model revealed a significant increase in the expression of Fra-1 in the ipsilateral brain cortex, which was in parallel with increase in the expression of active caspase-3. With immunofluorescence double-labeling, Fra-1 was colocalized with active caspase-3 and with NeuN, a neuronal marker. In an in vitro cell injury model, H2O2 exposure induced cell apoptosis and reduced cell viability and at the same time, a similar increased expression of active caspase-3, p53 and Fra-1 was found in PC12 cells. Down-regulation of Fra-1 through transfection with Fra-1 siRNA remarkably elevated cell viability, reduced the expression of active caspase-3 and p53, and decreased apoptosis of PC12 cells after H2O2 exposure. Taken together, present findings suggest that Fra-1 may be involved in the induction of neuronal apoptosis through up-regulating p53 signaling pathway and that this action may contribute to the secondary neuropathological process after TBI.