To better understand the pathogenesis of herpes simplex virus type 1 (HSV-1) infections of the nervous system, concentrations of F(4)-neuroprostanes (F(4)-NP) and F(2)-isoprostanes (F(2)-IP) in the murine brain were determined following intracerebral inoculation of HSV-1 or normal saline. F(4)-NP are highly selective, quantitative markers of neuronal oxidative damage, while F(2)-IP are markers of oxidative damage to brain tissue not limited to a certain cell type. In contrast to saline-treated control animals, HSV-1-infected animals developed encephalitic symptoms associated with severe inflammation, widespread HSV-1 protein expression, and significantly elevated F(4)-NP and F(2)-IP levels in the brain. Survivors of acute HSV-1 infection showed no encephalitic symptoms 2 to 3 weeks following virus inoculation. Brain tissue derived from mice euthanized 2 month after virus inoculation demonstrated expression of HSV-1 latency-associated transcripts without detectable HSV-1 protein expression. However, brain tissue from these animals showed focal chronic inflammation, moderately elevated F(2)-IP levels, and normal levels of F(4)-NP. These observations provide novel biochemical evidence that oxidant tissue injury is a mechanism underlying neuronal damage during acute HSV-1 encephalitis and suggest that oxidative damage to tissue may continue in the mammalian brain until at least several weeks after recovery from the symptomatic phase of HSV-1 infection.