Neurologic dysfunction and neuropathology are common findings in patients infected with HIV and in cats infected with feline immunodeficiency virus (FIV). The pathogenesis of lentivirus-associated alterations in the central nervous system (CNS) is multifactorial. Because seizures, alterations in memory, and behavioral changes are clinical manifestations in adults and children infected with HIV, we explored the possibility that changes in neuronal structure may occur in the hippocampus. To do this, we examined the dentate gyrus of FIV-infected cats, an animal model of HIV infection. Neuropathologic findings included gliosis within the hilus of the dentate gyrus and granule cell axonal sprouting. Using the Timm's method, which labels axons of dentate gyrus granule cells, abnormally high amounts of staining were observed in the inner one third of the molecular layer in 45% of FIV-infected cats (n = 11) and in none of the controls (n = 19). Prominent axonal sprouting was seen in three FIV-infected cats that were infected as kittens, suggesting that younger cats may be more susceptible. Axon reorganization of the dentate granule cells has been hypothesized to underlie complex partial seizure activity in human temporal lobe epilepsy. These results suggest that FIV infection causes granule cell axon reorganization in the hippocampus of cats. A similar neuropathogenetic mechanism may contribute to neurologic dysfunction in HIV-infected patients.