Gradual secondary injury processes, including the release of toxic reactive oxygen species, are important components of the pathogenesis of traumatic brain injury (TBI). The extent of oxidative stress is determined in part by the effectiveness of the antioxidant response, involving the enzymes glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Since nerve growth factor (NGF) may be involved in the initiation of antioxidant activity, we employed a controlled cortical impact injury model in rats to produce secondary hippocampal damage and determined the subsequent time course of changes in NGF production and GPx, CAT, and SOD activity in this brain region. Hippocampal NGF production showed a rapid increase with a biphasic response after TBI. NGF protein was increased at 6 h, plateaued at 12 h, declined by 7 days, and exhibited a second rise at 14 days after injury. Similar to NGF, hippocampal GPx activity also showed a biphasic response, increasing by 12 h, declining at 24 h, and exhibiting a second peak at 7 days. In contrast, increased CAT activity occured steadily from 1 day through 7 days after injury. SOD activity was decreased at 6 h after injury, and continued to decline through 14 days. The initial rise in NGF preceded that of CAT, and coincided with an increase in GPX and a drop in SOD activity. These data demonstrate a complex temporal spectrum of antioxidant enzyme activation following secondary brain injury in the hippocampus, and suggest a selective regulatory role for NGF in this response.