Survivors of herpes simplex encephalitis (HSE) experience intellectual impairment and an inability to store and recall information. Because the temporal lobes and associated limbic structures are central to storage and retrieval of memories, and are predominantly affected in adult HSE, injury to these areas is postulated to cause behavioral and learning disabilities. A previous study (Beers et al., 1993) demonstrated that intranasal inoculation of Lewis rats with herpes simplex virus type-1 (HSV-1) induced acute partial complex seizures, and hemorrhagic and inflammatory lesions of the hippocampus and entorhinal cortex. Consequently, it was of interest to determine whether rats that had recovered from HSE had limbic system-associated memory impairments. Therefore, rats were evaluated when signs and symptoms of encephalitis were no longer apparent using an eight arm radial maze to assess the acquisition and retention of learned information. An allocentric-spatial location paradigm revealed HSV-1 infected rats performed at chance levels on both acquisition and retention which were statistically different from sham-inoculated controls. However, using an egocentric-spatial left/right discrimination task, infected rats performed statistically similar to sham-inoculated controls. Furthermore, HSV-1 nucleic acids were detected in the nuclei of neurons within the hippocampus and entorhinal cortex using in situ hybridization techniques. Of interest was the observation that rats with learning and memory deficits had no apparent histopathological or immunocytochemical evidence of antecedent CNS infection. This is the first experimental demonstration that HSV-1 can cause behavioral impairments in the absence of obvious inflammatory injury to the temporal lobe memory system.